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The relationship between the biological activity of drugs, expressed in international units, and their therapeutic efficacy. The authors discuss the implications of this relationship and consider how far bio-assay in terms of units can meet the demand. They also examine the use of international units in characterizing therapeutic preparations and the complications that arise when the unitage-efficacy relation is not constant.
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Bull. World Hlth Org.
Director, Lister Istitute of Preventive (^) Medicine, London Member of the Expert Committee on Biological Standardization of the World Health Organization Formerly Director, Department (^) of Biological Standards, National Institute (^) for Medical Research, London W. L. M. (^) PERRY, M.D. Director, Department of Biological Standards, National (^) Institute for Medical (^) Research, London Member of the Expert Committee on (^) Biological Standardization of the^ World Health^ Organization
Manuscript received in January 1953
SYNOPSIS The relation between the biological activity of (^) drugs, expressed in terms of international units, and their therapeutic efficacy is neither simple nor constant, (^) varying with the (^) patient, the (^) disease, and the drug, together with a number of other factors. Yet clinicians and (^) pharmaceutical manufacturers understandably demand as simple a relation as possible between unitage and efficacy. The authors examine the implications of that demand and consider how far bio-assay in terms of units can be adapted to meet it. For this purpose they select three substances whose standardization is under consideration by the WHO (^) Expert Committee on (^) Biological Standardization: adsorbed diphtheria toxoid, delay insulin, and corticotrophin. In^ their^ conclusions, they consider that unitage should be regarded simply as a statement of the amount of active principle present, and that it should be taken as an indication of efficacy only when the efficacy (^) depends on the content of active principle. Where different dosage-response relationships of an active (^) substance, and of the same substance (^) compounded to increase efficacy, entail the establishment of a standard for the "^ compound (^) ", the (^) unitage of that compound must be expressed in terms of the number of units of starting material compounded. (^) Finally, they consider that unitage, apart from indicating the amount of active substance, cannot be (^) very useful to the clinician in his estimate of a drug's efficacy.
A. A. MILES & W. L. M. PERRY
contain the active substance alone, or mixed or combined with other substances to make it safer or more effective in man. Between the International Standard, which is the vehicle of the unit, and the patient who is given the drug are interposed the custodian of the standard, the manufacturer, the authority controlling the quality of the drug, and the clinician; and for each of these the unit has a different signi- ficance. To the custodian of standards, it is the activity of a certain weight of the standard preparation; to the manufacturer and the controlling autho- rity, it is a measure of the potency of the raw material and of the finished product; and to the clinician, it is an indication of the dose of finished product that he will give to his patient. With some biologically assayed substances used in medicine the clinician has no direct concern with the unit. He uses the drugs as named preparations, the composition of which is prescribed by law or by recognized authority, and doses his patient by weight or volume. Thus, in current practice of active immunization, the unit, where it exists, stops short at the controlling authority. In the United Kingdom of Great Britain and Northern Ireland, a diphtheria prophylactic must contain 50 Lf of toxoid per ml (which is measured in terms of the
tenths of a millilitre of prophylactic as defined in the Regulations to the Therapeutic Substances Act, 1925, altering the volume given according to
By mouth it would be largely ineffective, and given even subcutaneously
the efficacy of the dose is determined by much^ more^ than the^ unitage;
With biological drugs whose dosage is measured in^ units, there^ is
A. A. MILES & W. L. M. PERRY
In pursuit of their (^) general policy of (^) making standards for immunizing
formol toxoid. A purified preparation was chosen, as it is chosen whenever possible for all international standards, to avoid any (^) complication in (^) assay
There can, of course, be no certainty that a standard as established does not contain active impurities that will invalidate (^) assay of (^) test preparations,
of the treated material with a control (^) preparation of (^) plain toxoid.
have only a restricted use. In many hands, the dosage-response lines for plain purified toxoid and adsorbed toxoids are not parallel. The dosage-
be substantially parallel; and a standard for this group of toxoid preparation
and properly so, the standard for the basic material of all preparations of
It will be simplest to consider first a hypothetical case. Let us suppose
of high efficacy in man is produced, and its dosage-response line is parallel
as a measure of potency which must (^) appear on the label. If 1 Lf of (^) toxoid,
power of 100 Lf of plain toxoid, what is the unitage of the toxoid in the
unit. This contradiction must be avoided at all costs because to admit it
BIOLOGICAL POTENCY AND THERAPEUTIC EFFICACY
the contained toxoid is misleading and deprives the manufacturer of a legitimate right to indicate the clinical value of his (^) product. The argument, however, has little force unless it is hoped to make unitage an indication of efficacy in man-an impossible task because the unitage-efficacy relation is highly variable and at best can^ be^ stated only in general terms.
There would seem to be three possible courses open:
plain toxoid, and by other methods (a new name, suggested dosage in
proved efficacy.
(b) To omit designation of amount by units, and to advise the clinician
in this case would presumably lay down specifications for the product in terms of units of plain toxoid.
ration of the prophylactic itself. This course entails the establishment of a
The third course may recommend itself as a means of establishing a
efficacy relation already fixed in the cliniciat's mind for plain toxoid. It
result in the very contradiction it is designed to avoid. Even if the new
for some (^20) years, and the (^) Expert Committee on (^) Biological Standardization has decided to use it as the basis of an international unit for adsorbed toxoids.
basis for (^) assigning unitage to the (^) recently established International Standard
unit is such as to make the unitage-efficacy relation as convenient for the
The weight of unit activity of plain toxoid might be decided on the
BIOLOGICAL POTENCY AND THERAPEUTIC EFFICACY
by the conversion of 1 International Unit (IU) of insulin. It should be noted that it is not the activity of any preparation of protamine zinc insulin
is a complex of inconstant composition and the unit must be related to a unique preparation of the complex (i.e., to the international standard). An (^) analogous procedure is also valid for the (^) proposed standard for (^) globin
Provisional British Standard for Globin Zinc Insulin.2 It should also be
insulin or globin zinc insulin does not, of course, make the establishment
fulfilled.
The recent history of certain preparations of ACTH is (^) instructive. There are various ways of preparing ACTH from pituitary glands, most of which result in a dry powder soluble in water or saline; the potency of all
international units. The situation became complicated (^) by a report that (^) batches of (^) plain
had the same international unitage; they were also apparently equipotent
ACTH were tested (^) intramuscularly in rats, the potency ratio would also
A. A. MILES & W. L. M. PERRY
For the purpose of discussion, we may assume that the difference in fact lies in the route of injection, and not in some species difference in response between man and rats. We are then faced with two problems. First, the interpretation of a change in the potency ratio of two preparations, assayed in the same animal by the same general method of ascorbic-acid depletion,
and, secondly, the difficulty of expressing efficacy in terms either of unitage or of differently named preparations. Strictly speaking, the change from the intravenous to the intramuscular route in the rat is a change of biological
heterogeneity of the test and standard preparations. (A simple explanation of the heterogeneity would be a difference in the solubility of the two pre-
that no valid potency-ratio exists, and that potency can only be expressed in terms of certain fixed conditions of assay. This is a well-recognized limitation. It can^ be^ ignored when^ heterogeneity^ causes only relatively small changes of the potency ratio. For example, it was noticed 4 that the
assays of preparations of benzylpenicillin, and these are attributed to
penicillin G; but, once^ again, the^ difference^ between the^ two^ potency ratios is small-of the order of (^1) % or (^) 20% only-and can be ignored.
mined, some definition of^ the^ circumstances in which^ the assay is to^ be carried out becomes essential, with a consequent restriction in the validity of the potency ratios obtained. The interpretation of these potency ratios may be made less ambiguous if^ the standard preparation is homogeneous. Thus heterogeneous vitamin-D preparations are assayed against a pure
vitamins; but even with this improvement the assay of vitamin D^ is usually
according to the intended use of the vitamin preparation in man or fowls. A heterogeneity of ACTH preparations, which results in a fourfold difference in potency ratio when two different routes of injection are used in the^ rat
that gives the most useful potency-ratio must be defined; and it may be necessary to establish a standard preparation for the new type of ACTH.
potency-ratio would be obtained by the intravenous than by the intra-
A. A. MILES & W. L. M. PERRY
presumably lost in intravenous^ administration.^ Secondly,^ the^ proposed unit, which is clearly not the international unit, should be the activity of a given weight of a standard preparation of the new ACTH; and in this case, " activity " must be qualified, as unitage would be qualified on the label, by the words " intramuscular route ". Furthermore, unless assay in
route of injection would have to be established in the test animal. The relation of the proposed new unit to the existing international unit
international unit were formally tied to assays by the intravenous route
assay in terms of material standards.
when standards are established for^ families^ of^ substances.^ Thus^ rats or
Our analysis of these three problems illustrates the pharmaceutical
BIOLOGICAL POTENCY AND THERAPEUTIC EFFICACY
or in part, their explicit statement may at least stimulate the formulation of the correct (^) principles.
paration of a drug given in a certain way, measured in terms of (^) another
The nearest approach to a direct (^) relation would be obtained by assaying
produce the desired effect. This conclusion is not inconsistent with the concept of the (^) unit of bio-
BIOLOGICAL POTENCY AND THERAPEUTIC EFFICACY
Cliniciens et fabricants demandent qu'un rapport aussi simple que possible soit etabli entre l'activite d'une substance^ titr6e par voie^ biologique, indiquee en unit6s internatio- nales, et son efficacit6 th6rapeutique. L'objet de cet article est d'examiner cette requ8te et la facon dont les^ titrages biologiques pourraient etre concus pour la satisfaire. L'unit6 internationale d'activit6 revet une signification differente pour le laboratoire charge de l'entretien et de la distribution de l'etalon, pour le fabricant, l'administration de contr6le et le m6decin. Ce demier est habitue, pour certains medicaments tels que l'insuline par exemple, A estimer en unites la dose que le cas A traiter exige. Pourtant la dose n'est pas toujours une indication de l'effet. Le rapport entre la teneur en unit6s d'une preparation et son efficacite therapeutique n'est ni simple ni constant. La meme quantit6 d'insuline peut Wtre inactive par voie orale^ ou etre lethale par voie sous-cutanee, en periode de crise d'hypoglycemie. Pour les antibiotiques courants ou des serums anti- bacteriens, le clinicien doit prendre en consideration divers facteurs, tels que la nature de l'agent pathogene, le stade de l'infection, sa localisation, la voie d'administration. S'il s'agit de pr6parations-retard (PAM, insuline-protamine-zinc, par exemple) ou d'autres preparations dans lesquelles la substance active est m6lang6e A d'autres qui modifient son activite, le rapport entre unit6 et efficacit6 est encore plus complexe. Les auteurs exposent les problemes qui se sont poses A^ ce sujet, au Comit6 d'experts pour la Standar- disation biologique, de 1'OMS, pour trois preparations dont la standardisation est A l'etude: l'anatoxine diphterique adsorbee, les insulines-retard et la corticotrophine. La necessite d'etablir une unite d'anatoxine dipht6rique adsorbee est n6e du fait que les courbes dose-reponse d'anatoxine simple purifi6e et d'anatoxine adsorb6e ne sont pas paralleles. Si l'on ajoute A^ une substance active^ un^ adjuvant, en l'occurrence l'alumi- nium. qui intensifie considerablement son activite, quelle unit6 faut-il attribuer A cette preparation? Renoncant A^ la solution qui consistait A^ d6finir l'unite, pour chacune de ces preparations, comme la quantite produisant le meme effet physiologique, le comit a decide de partir de l'unite d'anatoxine adsorbee qui existait deja comme etalon national dans un pays et qui servira de base A l'etablissement de l'etalon international, et de d6finir l'unite de l'Etalon International d'Anatoxine Antidiphterique Simple, comme la quantite de cette derniere substance contenue dans une unit6 d'anatoxine adsorbee. Ainsi, pour obtenir le meme effet physiologique, il faudra un plus grand nombre d'unites d'anatoxine simple que d'anatoxine adsorb6e. Jusqu'A maintenant, la teneur en unites des pr6parations d'insuline-retard a ete indiquee d'apres la teneur en unites d'insuline soluble presente. Si l'on r6ussit A^ etablir un etalon international d'insuline-retard, quelle unite lui attribuer? I1 serait prejudiciable de fixer la teneur en unites d'apres l'action physiologique. L'unite devra plut6t etre d6finie
de voir ne resoud pas pour le clinicien la question du rapport unit6-efficacit6. C'est A lui qu'il incombe de savoir que 20 unites de preparation d'insuline-retard ont une activit diff6rente de celle de 20 unit6s d'insuline soluble. Quant A la corticotrophine, on s'est (^) aperqu que certaines pr6parations d'ACTH administrees sous forme retard, par voie intramusculaire, etaient quatre fois plus actives que 1'ACTH injectee par voie intraveineuse. Comment etiqueter les preparations d'ACTH les plus actives? Apres avoir discute la question de (^) l'heterog6eneith de (^) ce systeme biolo- gique particulier et mentionn6 les solutions proposees, les auteurs suggerent que les preparations d'activit6 quadruple portent une etiquette indiquant ce fait, et qu'un papillon, joint A l'emballage, y rende le medecin attentif. Ces exemples illustrent les probl6mes qui peuvent surgir, interessant ala fois le medecin, le fabricant, l'autorit6 de contr6le et le biologiste charge du titrage. Pour les r6soudre, il y a lieu de tenir compte de certains principes, dont les principaux sont r6sumes ci-dessous: 2
14 A. A. MILES &^ W. L. M. PERRY
a) Une distinction claire doit etre etablie entre activite et efficacite th6rapeutique. La premiere est etablie par rapport A un etalon, selon une m8me m6thode et par rapport A un meme systeme biologique. L'efficacite pour 1'homme, qu'il est impossible d'etablir par un essai biologique, est beaucoup moins precise. b) Le rapport entre activit6 et efficacit6 est tres variable, car il n'est pas possible d'effectuer des essais syst6matiques sur des patients; et, si c'etait faisable, les resultats ne seraient pas constants. c) La teneur en unit6s n'indique que la quantit6 de principe actif presente; elle n'indique qu'indirectement l'efficacite virtuelle de la preparation. d) Tout changement dans l'activite, qui n'est pas du A une modification reelle du nombre d'unites dans la^ preparation ne^ doit^ pas etre exprimee en^ termes^ d'unites,^ mais par tout autre moyen convenable (changement du nom ou des qualificatifs de la prepa- ration). II appartient au medecin de se tenir au courant des changements qui surviennent et A I'autorit6 de controle d'attirer l'attention sur la signification therapeutique de l'indi- cation des unites figurant sur l'etiquette. e) II^ y a^ lieu de^ choisir l'unite^ de^ faQon^ que^ les doses^ th6rapeutiques^ courantes cor- respondent A des nombres peu eleves. f) Dans le cas ou les rapports dose-reponse d'une substance et d'une preparation de cette substance sont differents, l'unite de la preparation doit etre d6finie conmme la quantite contenant une unit6 de la substance-mere. II (^) resulte de (^) l'examen du concept d'unit6 (^) que ce dernier n'a que peu d'utilit6 pour indiquer au clinicien l'efficacit6 d'une preparation. I1 importe de sauvegarder le principe des essais biologiques et l'expression de I'activite en unites par rapport a un etalon, car de ce principe d6pend la mise au point de substances biologiques exactement definies et sfires.