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Bull. Org. mond. Sant| 1953, 9, 1-
Bull. World Hlth Org.
BIOLOGICAL POTENCY AND ITS RELATION
TO THERAPEUTIC EFFICACY
A. A. MILES, M.D., F.R.C.P.
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.
The most practical and widespread use of an international unit of
biological activity is in characterizing therapeutic preparations, which may
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
unit of diphtheria antitoxin), and the clinician is accustomed to use so many
tenths of a millilitre of prophylactic as defined in the Regulations to the Therapeutic Substances Act, 1925, altering the volume given according to
whether he uses plain formol toxoid or one of the adsorbed toxoids. But
in the case of insulin, for example, the unitage is shown on the label of the
container used by the clinician, who is accustomed to estimate the patient's
requirements in terms of units. The effect of a given dose of insulin in the
patient is not, however, solely determined^ by the^ number of units it^ contains.
By mouth it would be largely ineffective, and given even subcutaneously
during a hypoglycaemic crisis it might kill rather than cure. In other words,
the efficacy of the dose is determined by much^ more^ than the^ unitage;
unitage is only one of an immense number of factors the clinician must
recognize in treating the patient.
These factors change in number and importance with each^ patient,
each disease, and each drug. Most of these factors are of course equally
important in the use of "^ biological "^ drugs (i.e., those standardized by
bio-assay) and of those which are defined chemical substances; thus the
administration of a given dose of^ magnesium sulfate^ will^ purge if^ given
orally and will kill if given intravenously. This difference is so obvious
that comment appears superfluous; nevertheless it tends to be overlooked.
The proper use of a given amount of a drug is the responsibility of the
clinician; and all he needs^ to^ know^ of^ the^ particular preparation he^ uses^ is
its composition and the amount in the container.
With biological drugs whose dosage is measured in^ units, there^ is
another complication, because, though unit potency is properly only a
designation of the amount of active substance, it is also a measure of its
A. A. MILES & W. L. M. PERRY
are definable in terms of the International Unit of Diphtheria Antitoxin.
In pursuit of their (^) general policy of (^) making standards for immunizing
antigens, the Expert Committee on Biological Standardization established
a standard for diphtheria toxoid, which is a purified preparation of dry
formol toxoid. A purified preparation was chosen, as it is chosen whenever possible for all international standards, to avoid any (^) complication in (^) assay
that might arise from the presence of synergists or inhibitors in the material.
There can, of course, be no certainty that a standard as established does not contain active impurities that will invalidate (^) assay of (^) test preparations,
but the purer the standard, the better the chance of avoiding them. Moreover,
a basic standard of this kind makes it possible to measure the effect of
added substances that^ might be^ useful^ as^ potentiators in^ therapeutic pre-
parations of a substance; for example, the great enhancement of anti-
genicity of diphtheria toxoids by aluminium was determined by comparison
of the treated material with a control (^) preparation of (^) plain toxoid.
In practice, however, the standard for plain toxoid has been proved to
have only a restricted use. In many hands, the dosage-response lines for plain purified toxoid and adsorbed toxoids are not parallel. The dosage-
response lines for crude toxoids and adsorbed toxoids, however, appear to
be substantially parallel; and a standard for this group of toxoid preparation
is to be made-the International Standard for Diphtheria Toxoid, Adsorbed.
Since the greater bulk of diphtheria prophylactic in use today is adsorbed
toxoid, the standard for plain toxoid will be little used, though it remains,
and properly so, the standard for the basic material of all preparations of
diphtheria toxoid. The^ question at^ issue here^ is the^ proper relation^ of the
unitage of the standard preparations of plain and adsorbed toxoids.
It will be simplest to consider first a hypothetical case. Let us suppose
that by adding a new adjuvant to purified toxoid a diphtheria prophylactic
of high efficacy in man is produced, and its dosage-response line is parallel
to that of the International Standard for Diphtheria Toxoid, Plain; and
that the International Unit of toxoid is prescribed by controlling authorities
as a measure of potency which must (^) appear on the label. If 1 Lf of (^) toxoid,
when mixed with the new adjuvant, has in guinea-pigs the immunizing
power of 100 Lf of plain toxoid, what is the unitage of the toxoid in the
new preparation? As an indication to the clinician of its efficacy, clearly
it should be 100 times that of the same amount of plain toxoid; but equally
clearly it is contradictory to define a unit as a given weight of a standard
preparation of plain toxoid and, having compounded this amount of^ plain
toxoid with an adjuvant, then to consider 1/100th part of this weight as a
unit. This contradiction must be avoided at all costs because to admit it
would be to deny one of the main principles-the invariability of the unit-
upon which assay in terms of standards is based.3 The inventor of the new
prophylactic has increased the efficacy of the diphtheria toxoid, but he
cannot be said to have increased its unitage.
BIOLOGICAL POTENCY AND THERAPEUTIC EFFICACY
It could be argued that to insist on designation of unitage in terms of
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:
(a) To designate the strength of the new prophylactic in units of
plain toxoid, and by other methods (a new name, suggested dosage in
units, advice in accompanying leaflet) to advise the clinician of its im-
proved efficacy.
(b) To omit designation of amount by units, and to advise the clinician
as in (a), expressing dosage in volume or weight. The controlling authority
in this case would presumably lay down specifications for the product in terms of units of plain toxoid.
(c) To label the new prophylactic in units based on a standard prepa-
ration of the prophylactic itself. This course entails the establishment of a
new standard preparation, and the assignment of a unitage thereto.
The third course may recommend itself as a means of establishing a
unit of the new prophylactic which would have the same immunizing
efficacy in man as one unit of plain toxoid, thus maintaining the unitage-
efficacy relation already fixed in the cliniciat's mind for plain toxoid. It
is not, however, justifiable to do so because the prophylactic owes its efficacy
primarily to the contained diphtheria toxoid, and such a course would
result in the very contradiction it is designed to avoid. Even if the new
prophylactic could be considered^ as a^ new^ substance-for^ example, a true
compound in the sense that procaine penicillin is a chemical compound-a
revaluation of the unitage of toxoid in this way would still be contradictory.
With this hypothetical case in^ mind, we^ may now return to the problem
of assigning a unitage to the proposed standard preparation of diphtheria
toxoid, adsorbed. The problem differs, however, in an important but not
essential respect. A unit of adsorbed toxoid has been in use in Germany
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.
We have in this case, therefore, to start with the unit of adsorbed toxoid as a
basis for (^) assigning unitage to the (^) recently established International Standard
for Diphtheria Toxoid, Plain. It should be noted that the size of the German
unit is such as to make the unitage-efficacy relation as convenient for the
clinician as possible, in that a small, but not too small, number of units (of
the order of 10 to 20) is required for the usual prophylactic dose.
The weight of unit activity of plain toxoid might be decided on the
same grounds, i.e., it might be made the weight of the standard preparation
BIOLOGICAL POTENCY AND THERAPEUTIC EFFICACY
by the reasoning we have developed in the case of diphtheria toxoids,
the unit of activity of protamine zinc insulin should be that weight of
the international standard preparation of protamine zinc insulin made
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
made by the conversion of 1 IU of insulin, because 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
zinc insulin and has in fact already been followed in establishing the
Provisional British Standard for Globin Zinc Insulin.2 It should also be
noted that the^ procedure does^ not^ simplify the^ unitage-efficacy relation for
the clinician. It merely preserves the relation he has already worked out
for himself by clinical experience with soluble and delay insulins. In other
words, 20 units of^ protamine zinc insulin are known by the clinician to
have a much longer but less profound hypoglycaemic effect than 20 units
of soluble insulin; the clinician is aware that equivalence of unitage does
not imply equivalence of efficacy.
The proposed relation of unitage for soluble and either protamine zinc
insulin or globin zinc insulin does not, of course, make the establishment
of separate standards for these substances unnecessary. They are needed
not only as^ standards for^ delay action^ in^ the^ test^ animals, but also to make
valid the assay of the insulin activity of these preparations by providing
a standard of a like substance, so that the "^ hypothesis of similarity "1 is
fulfilled.
Corticotrophin
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
such preparations is designated in international units. To prolong the
action of intramuscular ACTH, certain pharmaceutical preparations have
been devised, including ACTH in a gel; these also are labelled in contained
international units. The situation became complicated (^) by a report that (^) batches of (^) plain
ACTH prepared by a certain method were about four times as effective
as ACTH prepared by other processes, when given intramuscularly in
man, though both preparations, assayed by intravenous injection in rats,
had the same international unitage; they were also apparently equipotent
in man by the intravenous route. This suggests that if the two kinds of
ACTH were tested (^) intramuscularly in rats, the potency ratio would also
be 4:1, as compared with a ratio of 1:1 obtained by the intravenous tech-
nique; some preliminary tests appeared to confirm this suggestion.
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,
when the injection route is changed from^ intravenous to intramuscular;
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
system; therefore any concomitant^ change in^ potency ratio^ must^ be due to
heterogeneity of the test and standard preparations. (A simple explanation of the heterogeneity would be a difference in the solubility of the two pre-
parations in^ the^ fluids of^ the^ muscle.) This^ heterogeneity implies at once
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
potency ratio of two preparations of digitalis differed according to whether
they were assayed in cats by continuous infusion or^ by a series of interrupted
injections, because the^ proportion of^ rapidly^ and^ slowly acting^ glycosides
in the two preparations was different; however, the variation in potency
ratio was only of the order of a factor of 1.2 or less, and was consequently
ignored. Similarly, heterogeneous potency-ratios have been recorded^ in
assays of preparations of benzylpenicillin, and these are attributed to
differing contamination of the preparations with penicillins other than
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.
When heterogeneity is large, and its nature and degree are not deter-
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
preparation of vitamin D3, which is the International Standard for all D
vitamins; but even with this improvement the assay of vitamin D^ is usually
prescribed in^ one^ of^ two^ biological systems-either the^ rat or^ the^ chick-
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
assay, is^ likewise^ impossible to^ ignore. Consequently,^ the^ route^ of^ injection
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.
As regards the route of injection, it is arguable that the more legitimate
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
man were prescribed, an equally large change in efficacy with change of
route of injection would have to be established in the test animal. The relation of the proposed new unit to the existing international unit
also presented difficulties. The new unit would be redundant unless the
international unit were formally tied to assays by the intravenous route
in the rat; and such a course^ would be^ contrary to^ the^ principles^ of^ bio-
assay in terms of material standards.
It must be admitted that in practice something very much like it occurs
when standards are established for^ families^ of^ substances.^ Thus^ rats or
chicks are used in vitamin-D assays according to the proposed recipient of
the vitamin-man or bird. But the practice rests on a well-established
difference between the responses of^ two^ widely separated species, both of
economic importance. A^ difference^ in^ route^ of^ administration in^ the^ same
animal-a difference, moreover, which is only one of the many variables
in treatment with ACTH that might modify its efficacy-is hardly a
substantial reason for^ re-defining or^ formally qualifying^ an^ international
unit. Nor, in our opinion, is it a reason for establishing a " local " unit
differing from the international unit only (as far as present evidence goes)
by reason of route of^ administration.^ We^ would^ suggest^ that,^ until^ much
more evidence as to the difference between the old and new types of ACTH
has been obtained, the solution to the problem lies, not in recognizing
new units, but in finding a name^ which^ clearly distinguishes the^ two^ pre-
parations. Thus, if the^ new^ ACTH^ were^ labelled^ as^ "^ Corticotrophin,
H.I.M.", meaning "^ high intramuscular activity ", the contents could be
defined in terms of international units, and it^ could^ be^ left^ to^ the^ clinician
(informed by leaflet, for^ example)^ to^ recognize^ that^ only^ one^ quarter^ of^ the
unitage of ordinary ACTH was required when using this material. This
procedure is strictly analogous to that^ at^ present adopted for^ the^ protamine
zinc insulin; it would, moreover, be consistent with the creation of a standard
for the new material, should further evidence warrant it.
Unitage-Efficacy Relationship
Our analysis of these three problems illustrates the pharmaceutical
difficulties that may arise in^ the^ use^ of^ a^ biologically standardized^ drug.
The claims of the clinician, the controlling authority, the manufacturer,
and the assayist may conflict, and there is no^ general agreement about
whose opinion should have the^ greatest weight in these^ matters.^ The
conclusions implicit in our arguments may serve as guiding principles in
BIOLOGICAL POTENCY AND THERAPEUTIC EFFICACY
resolving these conflicts. If they prove to be unacceptable, either wholly
or in part, their explicit statement may at least stimulate the formulation of the correct (^) principles.
1. A clear distinction must be made between potency and therapeutic
efficacy of a drug.
Potency is the activity of a drug measured in terms of a similarly consti-
tuted standard preparation, both being tested in the same way in the same
biological system. Therapeutic efficacy is the activity in man of one pre-
paration of a drug given in a certain way, measured in terms of (^) another
preparation of the drug given in the same way, or of the same preparation
given in another way. Since assay in man is usually impracticable, the esti-
mation of efficacy is necessarily much less accurate and precise than the
estimation of potency, which is commonly determined on biological systems
susceptible to experimental control.
2. The relation between potency and efficacy is highly variable, even
with one preparation of a drug.
The nearest approach to a direct (^) relation would be obtained by assaying
the potency of a drug in the diseased human subject. This approach was
achieved, though the method of assay was imperfect, in the standardization
of liver extracts in patients with pernicious anaemia. In most cases, however,
it would be impracticable, and it would nearly always be ethically undesir-
able. The clinician and the controlling authority (which represents the
interests of both clinicians and their patients) have therefore always to
make some translation of stated potency of a drug into their own idea of
its efficacy in the patient. Even if the drug were assayed in diseased man,
the variable manifestations of the disease in different men would always
entail adjustment of this nearly direct relation of potency to efficacy.
3. In the description of a drug for clinical use, the unitage is to be
regarded solely as a statement of the amount of the active principle present;
only indirectly is it an indication of the capacity of the preparation to
produce the desired effect. This conclusion is not inconsistent with the concept of the (^) unit of bio-
logical activity, which is defined as the specific activity of "^ x " grams of a
standard preparation. If a controlling authority desires to prove that a drug
contains ten units of a substance, it is in effect demanding to know that the
amount of active principle is the same as that in "^ lOx "^ grams of the standard
preparation of the substance; and because chemical and physical methods
for characterizing the substance are inadequate, biological activity happens
to be the means whereby the measurement is made. The secondary status
of biological activity in this comparison is well illustrated in the assay of
vitamin-A preparations, where unitage of a specimen can still be stated in
terms of the standard preparation, but where the link between the two is
spectrophotometric. This being so, a unit, though it is a unit of biological
BIOLOGICAL POTENCY AND THERAPEUTIC EFFICACY
RItSUMIt
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
comme la quantite de la preparation contenant une unite d'insuline soluble. Cette facon
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.
REFERENCES
- Jerne, N. K. & Wood, E. C. (1949) Biometrics, 5, 273
- J. Pharm., Lond. 1952, 4, 382
- Miles, A. A. (1949) Bull. World Hlth Org. 2, 205
- Miles, A. A.^ & Perry, W. L. M.^ (1950)^ Bull.^ World Hlth^ Org. 2,^655
