`
`THE JOURNAL
`
`OF THE
`AMERICAN MEDICAL ASSOCIATION
`
`EDITED FOR THE ASSOCIATION UNDER THE DIRECTION OF THE‘ BOARD OF TRUSTEES BY
`
`JOHN H. TALBOTT, M.D.
`
`VOLUME 177
`
`. JULY 8—I—~SbE«l7?f”17i31\51\I4]:73“I3fI{ .30
`1961
`
`AMERICAN MEDICAL ASSOCIATION, CHICAGO 10
`
`Astrazeneca Ex. 2118 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01324
`
`
`
`34
`
`I.A.M.A., July 8, 1961
`
`Forecasting Drug Effects in Man from
`Studies in Laboratory Animals
`
`John T. Litchfield, Jr., M.D., Pearl River, N.Y.
`
`AND IN HAND with the growth of medical
`research has been the steady increase in the
`number of new drugs introduced, and in the extent
`to which each drug is investigated in the laboratory
`and clinic. The primary objective of much of this
`investigation is to determine if and how the new
`drugs may be used safely in man. This is also a legal
`prerequisite to the sale of the drug, since, under the
`provisions of the Federal Food, Drug, and Cosmetic
`Act, a new drug cannot be marketed until its safety
`in man has been established. The method of study
`used to determine the safety of a new drug in
`laboratory animals is influenced by regulatory in-
`terpretations of this Act. However, in the face of
`the pressures created by the tremendous growth of
`such work, it is easy to lose sight of the real purpose
`of these studies. Thus, a restatement and reexami-
`nation of this purpose is in order.
`Studies on the safety of new drugs in laboratory
`animals are intended to develop knowledge which
`will help to protect the patients who are to receive
`the new drug by forewarning the doctor of its pos-
`sible dangers. If this basic purpose is clear, it is
`apparent that these studies must permit a prediction
`of what will occur when the drug is used in man. If
`this were not so, there would be no reason to con-
`duct these elaborate and costly studies.
`One may still ask, “On what evidence is the pre-
`dictive value of data from laboratory animals
`based?” Rather astonishingly, there is no good evi-
`dence to answer this question; instead, it is gener-
`ally assumed that such predictive value exists.
`It is true that many drugs have been shown to
`have a particular activity both in animals and in
`man. This is a very narrow aspect of the problem,
`however, because no drug has a single action, al-,
`though it may have a predominant one compared
`to all of the actions which it can exert. Thus, since
`every possible action of a drug must be evaluated,
`the task of showing the predictive value of animal
`studies is formidable. The literature discloses no
`example of a critical comparison of the total actions
`of 2 or more drugs observed in laboratory animals
`with the total actions later found in man. In fact,
`
`Director, Experimental Therapeutics Research Section, Lederle Lab0—
`mtories, Division of American Cyanamid Company.
`
`Experiments on animals are the most
`important source of data for predicting
`the eifects of administering a new drug
`to patients. Nevertheless, the predictive
`value of such experiments is limited. In
`the present retrospective study of 6 drugs
`of different types, it is shown that many
`of the most serious side effects that can
`
`result when a drug is given to man were
`not predictable from observations on dogs
`01' rats. From an initial list of signs of
`toxicity that could occur
`in man, 39
`physical signs were retained that could
`also he observed in the dog or the rat,’
`or both. Analysis showed that effects on
`man could be predicted better from ob-
`servations on dogs than from those on
`rats.
`‘
`
`the available evidence along these lines led Barnes
`and Denzf
`in their comprehensive review of
`methods for determining chronic toxicity, to con-
`clude that the conventional procedures for carrying
`out
`these studies in the laboratory are entirely
`empirical and have little scientific basis, and that
`extrapolation of the results of these studies to man
`is a matter of guesswork. If this indictment is cor-
`rect,
`then there is little purpose in most of the
`toxicity tests on new drugs which are performed on
`laboratory animals today, because the findings, in
`essence, are uninterpretable when they are applied
`to man.
`
`In View of the fact that apparently no one has
`previously attempted systematically to predict from
`laboratory data what would happen subsequently in
`man, a retrospective study of 6 drugs was under-
`taken.
`
`The drugs were selected because they met the
`following criteria: 1. Detailed studies in the rat,
`dog, and man were available (500 case reports,
`minimum for man)‘. 2. All studies were performed
`within the past 7 years. 3. All studies were per
`formed under comparable conditions with respect
`to the standards observed. 4. All drugs were un-
`related in chemical structure.
`
`104
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`Astrazeneca Ex. 2118 p. 2
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`
`
`
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`Vol. 177, N0. 1
`
`FORECASTING DRUG EFFECTS~LITCI-IFIELD
`
`35
`
`The drugs were chosen from the following
`classes: antibacterial, tranquilizer or central nervous
`system depressant, glucocorticoid, and antialcoholic.
`The studies in animals comprised acute experi-
`ments, as well as chronic experiments of 1 to 3
`months’, 6 months’ (dogs), and 1 year’s duration
`(rats). All studies of 30 days or longer included de-
`tailed gross and microscopic pathological examina-
`tions. These studies, which were planned and con-
`ducted jointly by pharmacologists and pathologists,
`were directed toward exceeding the tolerance of the
`animals for the drug, and every effort was made to
`discover the actions of the drug by careful obser-
`vation of the animals. The number of dogs used was
`relatively small compared to rats; consequently, ob-
`servation of the dogs was more comprehensive than
`that of the rats. In the case of man, case reports
`available varied from 800 to 7,500, depending on
`the drug under investigation (average 3,300 ).
`All
`the available data on each drug were ex-
`amined, and every drug effect which had been
`noted was tabulated according to species studied.
`At
`this point, several requirements became ap-
`parent:
`1. The incidence of drug effects in animals was
`not comparable to the incidence of drug effects in
`man because, in the former, dosage was pushed to
`the point of intolerance while, in the latter, no such
`procedure was or could be followed. It was neces-
`sary, therefore, to disregard incidence; either a drug
`effect occurred or it did not.
`
`2. A limitation on the vocabulary of drug effects
`was necessary in order to eliminate synonymous
`terms. Forexample, there are many possible kinds
`of anemia and also a variety of ‘ways in which
`anemia can be detected. Therefore, for the purpose
`of this study, it was suflicient to use the general
`term “anemia” rather than a variety of other de-
`scriptive terms.
`3. It is possible to observe only physical signs in
`animals, not symptoms. This required eliminating
`from the tabulations those symptoms recorded in
`man. Similarly, any physical sign which could not
`occur in an animal also was eliminated. For ex-
`
`»
`
`ample, the rat cannot vomit, although dog and man
`may. Physical signs in this study included results of
`laboratory examinations.
`4. It was found to be impossible to judge the
`relative importance of one physical sign over an-
`other. Thus, anemia may be fatal in one case but
`insignificant in another.
`Under these requirements, the data on each drug
`could be tabulated as shown:
`Eat Dog Man
`1
`Impaired reflexes, hypotension, ataxia,
`. . . . . . . . . .. +"‘ +
`+
`.
`.
`.
`decreased activity . . . . . . . . . . . . .
`. . . . . . . . .
`Weight loss . .
`.
`. . . .
`. .
`.
`.
`. . . . . . . . . . . . . . . . . . . . . . .
`. . . . . .. +
`+ —i
`Tremors . . .
`.
`. .
`.
`.
`.
`. . . .
`.
`.
`. . . . . . . . . . . . .
`. . . . . .
`. . .
`. .
`. . . . . . . . .
`..
`+
`+
`Ptosls, urinary incontinence, catatonia . . . . . . . . . . . .. +
`..
`..
`Lacrimation . . . . . . . . .
`.
`. . .
`. . . . . . . . . . .
`. . . . . . . . . . . . . . . . . .
`. .
`. .
`+
`. .
`Diarrhea . . . .
`. . . . . . .
`. .
`.
`.
`.
`. . . . . . . . .
`. . .
`. . .
`. . . . . . . . . . . . , .
`. ..
`..
`..
`+
`*+=occurrez1ce
`t~::not. observed
`
`105
`
`From these tabulations a complete list of physical
`signs was prepared, and an appropriate entry was
`made under each species to indicate the presence
`or absence of a sign produced by each drug. Final-
`ly, it was required that the list include only those
`physical signs which were noted at least once in the
`rat or dog. This eliminated 16 physical signs which
`were reported in man but which had no counterpart
`in either the rat or dog. Each one of the remaining
`39 different physical signs had been found with one
`or more drugs in either or both rats and dogs.
`Finally, the data on the 39 different physical signs
`were classified so that an appropriate entry for each
`physical sign and each drug was made under one of
`the following classes:
`'
`
`Meaning
`Class
`Sign not elicited in rat, dog, or man
`Absent‘
`Sign elicited only in rats
`Rat
`Sign elicited only in dogs
`Dog’
`Sign elicited only in man
`Man
`Sign elicited in both rats and dogs but not man
`Rat, dog
`Sign elicited in both rat; and man but not dog
`Rut, man
`Sign elicited in both dogs and man but not rat
`Dog, man
`Rat, dog,1nan Sign elicited in rats. dogs, and man
`
`The incidence of physical signs noted in each of
`these classes was then determined. Tests of sig-
`nificance were made by calculating (Chi)“’ as
`S (observed—eXpected) 2.
`expected
`
`Results
`
`VVhen all of the physical signs observed from use
`of the 6 drugs in rats and dogs were collected,
`synonymous terms consolidated, and signs which
`could not occur in all 3 species eliminated, the data
`were tabulated as shown in Table 1. It will be noted
`that for each physical sign, the 6 drugs must be
`accounted for in 2.01‘ more of the classes shown. For
`example, for the first
`line (weight
`loss) 2 drugs
`caused this sign in both rats and dogs but not in
`man, while 4 drugs elicited this sign in all 3 species.
`There are 8 classes in the tabulation because the
`data were treated as if coming from a 23 factorial.
`The “absent” class, representing those instances in
`which a drug failed to produce a given sign in
`any of 3 species, is by far the largest.
`to contrast
`The objective of this tabulation is
`those findings present in man with those findings
`not present in man. This is shown in Table 2, which
`compares the observed incidence of physical signs
`in the 4 classes excluding man with the correspond-
`ing 4 classes including man. The first line of the
`table shows that physical signs from use of the 6
`drugs were not observed 146 times in any of the
`3 species, while signs were observed only in man
`and not in rats or dogs 23 times. The over-all total
`of 234 represents the product of 6 drugs times 39
`physical signs. For each class the contribution to
`(Chi)2 is given. A large (Chi)“ value permits the
`inference that a correlation is present between the
`
`Astrazeneca Ex. 2118 p. 3
`
`
`
`36
`
`FORECASTING DRUG EFFECTS—LITCI-IFIELD
`
`].A.M.A., July 8, 1961
`
`different species. The (Chi)2 of 43.5 is significant,
`and results from the fact that
`the observed fre«
`quencies were quite diiferent in several cases from
`the expected value, which is calculated on the
`assumption that all classes are alike in relative
`frequency.
`[(Chi)* computed omitting the “absent”
`and “man” classes is 9.7, n : 2, and p<0.01.]
`Having established the fact
`that a significant
`relationship among the 3 species is present, the task
`is to discover the most effective way of utilizing
`this information to predict the carry-over of physi-
`
`Table 1.—Occurrence of 39 Physical Signs from
`Six Drugs in Three Species
`
`predicted to occur in man, 181 out of 234 (or 77%)
`of the predictions would have been correct.
`The remaining 4 methods consist of using physi-
`cal signs seen only in (2) rats, (3) dogs, (4) both rats
`and dogs, and (5) rats or dogs as the basis for pre-
`dicting their occurrence in man. Table 3 shows the
`results when these 5 methods were employed. The
`
`Table 2.—Summary of Occurrence of Physical Signs by
`Factorial Classes with Contributions to (Chi)2*
`Not Man
`(0hs.-
`Man
`(0hs.—
`,-———~k-——a Exn.)2 r-——-J*——--s Exp.)'-’-
`Class
`Observed
`Exp.
`Class
`Observed
`Exp.
`Absent
`146
`117
`Man
`23
`5.9
`Rut
`11
`0.4
`Rat, man
`1
`1.3
`Dog;
`16
`1.0
`Dog, man
`11
`(L0
`Rat, dog
`8
`(3.;
`Eat, dog
`17
`20.2
`and man
`
`Total
`Observed
`IE9
`12
`23
`25
`
`lU.|
`lill
`Totals
`* (Chi):-’ = 43.5, n : 3,13 <0.01.
`
`53
`
`33.4
`
`234
`
`first method uses the totals shown at the bottom of
`Table 2 and mentioned above. The second method
`utilizes the rat as a predictor. In the “not man”
`column, the “absent” and “dog” classes of Table 2
`are combined to give a total of 162 for the “not rat”
`class, and the “rat” and “rat, dog” classes are co1n~
`bined to give a total of 19 for the “rat” class. The
`values for the “man” column are obtained in a
`similar manner. VVhen the rat is used as the basis
`for predicting, 18 out of 53 (or 34%) of the physical
`signs observed in man were predicted correctly,
`which is a little better than the 23% which can be
`obtained without experimentation. However, 49%
`of the positive predictions made (18 out of 37) were
`correct, and this accounts almost entirely for the
`significant value of (Chi)?
`The remaining 3 methods given in Table 3 were
`similarly calculated. It was already noted in Table 2
`
`1
`
`.
`...'
`
`1
`
`1
`
`1
`
`1
`
`1
`1
`2
`
`.
`
`.
`1
`
`1
`...
`1
`2
`1
`
`2
`
`1
`
`1
`
`1
`1
`1
`1
`1
`
`.
`
`1
`1
`2
`
`. .
`
`.
`
`. .
`3
`1
`
`1
`
`4
`.. .
`1
`1
`
`2
`
`1
`
`1
`
`1
`2
`
`1
`
`.
`
`1
`
`1
`1
`1
`
`1
`
`. .
`..
`
`1
`1
`
`1
`1
`2
`
`..
`1
`
`1
`
`.
`
`. . .
`
`. . .
`
`
`
`. ..
`. ..
`. ..
`. ..
`. ..
`. . .
`
`.
`.
`
`. . . . . . ..
`.
`. .
`. . . . . . . .
`. ..
`
`Table 3.—Results of Five Different Methods of Predicting
`Occurrence of Physical Signs in Man
`Correct
`Predictions
`as % of Total
`r——— —/~~>—‘A\
`Predic-
`Incidence
`tions
`in Man Made
`.. .
`23
`
`Pradlct to carry
`Over to Man
`All signs
`Signs seen only
`in rats
`Signs seen only
`in dogs
`Signs seen only
`in rat and dog
`
`Signs seen
`in rat or dog
`
`Glass
`Not
`Class Man Man
`181
`Total
`Not rat.
`16-2
`Rat
`19
`Not dog
`137
`Dog
`24
`Not. rat
`and dog 173
`Rat and
`dog‘
`8
`Not rat_
`1-16
`or dog
`Rat or
`dog
`
`35
`18
`24
`29
`36
`17
`28
`
`30
`
`35
`
`(Cl1|)“
`. ..
`
`34
`
`53
`
`32
`
`57
`
`49
`
`55
`
`G8
`
`-1G
`
`19
`
`40
`
`30
`
`27
`
`that 23 physical signs were seen only in man. In this
`case, no basis existed for predicting these signs,
`since the drugs involved had failed to elicit the
`signs in rats or dogs. The objective, therefore, is to
`predict correctly as many of the remaining 30 signs
`as possible or,
`in other words,
`to maximize the
`correct predictions as per cent of total incidence in
`
`106
`
`Astrazeneca Ex. 2118 p. 4
`
`Rat,
`Rat Dog Dog.
`Rat
`and and and
`and
`AlJ-
`sent Rat Dog Dog Man Man Man ‘M an
`. ..
`'2
`4
`3
`4
`5
`4
`5
`3
`1
`3
`5
`2
`5
`5
`6
`2
`4
`3
`5
`3
`4
`1
`5
`'2
`3
`3
`3
`5
`5
`.’
`5
`4
`5
`4
`
`. . .
`1
`1
`1
`
`1
`
`.
`
`1
`
`. ..
`
`. .
`
`..
`
`. ..
`
`1
`
`1
`
`1
`1
`
`4
`4
`5
`2
`6
`5
`I46
`
`2
`
`1
`
`. ..
`I I
`
`.1
`
`2
`
`1
`I5
`
`8
`
`23
`
`I
`
`. .
`
`1
`
`1
`
`I7
`
`1
`
`[2
`
`Physical Signs
`Weightloss . . .
`.
`.
`.
`.
`.
`Wclghtgain
`.
`.
`.
`. . .
`Muscle atrophy . .
`. . . . . .
`1-Iyositis . . .
`.
`.
`.
`.
`.
`.
`Lympliocytopenia . . . . .
`Neutropenia .
`.
`.
`. .
`.
`. . . .
`.
`Leukopcnia ..
`. .
`.
`.
`Anemia .
`.
`. .
`.
`.
`.
`.
`.
`.
`Leukocytosis ..
`Hyperglyceinia ..
`Liverdairmge
`Jaundicc..... .
`Fatty liver
`.
`. .
`Polyrlipsia .
`.
`Polimria
`. ..
`. .
`Oliguria .
`. . . . . ..
`.
`.
`.
`.
`.
`Heinalsuria . .
`.
`Crystallurin or renal
`concretions
`.
`.
`. . . . . . ..
`Renal damage .
`. .
`.
`. . . . . . ..
`Gastroduodenal ulcr-.r
`.. ..
`Diarrhea .
`. .
`.
`. . . . . . . .
`Salivation
`
`. .
`.
`. .
`.
`.
`.
`.
`. .
`. ..
`Ataxia . .
`.
`Impaired reflexes
`Decreased activity ..
`'J.‘re1nors
`. . . . . .
`.
`.
`.
`.
`.
`.
`Ptosis .. .
`.
`.
`.
`.
`.
`.
`.
`. . ..
`..
`Catatonia .
`.
`.
`.
`.
`.
`.
`. ..
`. ..
`.
`.
`.
`Priapism
`. . . .
`.
`.
`.
`.
`. ..
`.
`.
`.
`Lacrimation . .
`.
`.
`. . .
`.
`Urinary incontinence . . ...
`Bacterial invasion .
`.
`. . . . ..
`Parasiticinvasion
`'l')ecreased thyroid
`. . ..
`. . . . .
`iunetion .
`.
`.
`.
`.
`.
`.
`.
`. . .
`Genital hypoplasia . .
`.
`Decreased adrenal function
`(cortical)
`. .
`.
`. . . . . .
`.
`.
`. . ..
`Hypotension ..
`.
`.
`.
`.
`. . ..
`Lungedenia ..
`.
`.
`.
`.
`.
`. ..
`Tachypnea . . .
`. . . . .
`.
`.
`.
`. . .
`.
`Totals . . . . .
`.
`.
`.
`.
`. . . . . . . ..
`
`
`
`
`
`cal signs from animals to man. Altogether, 5 diEer—
`ent methods are evident. The first is that it could
`be predicted thateither all or none of the physical
`signs would occur in man. This method represents
`the “no experimentation” rule: Either no experi-
`mental information on the rat or dog is available,
`or such information is ignored in the belief that
`there is no correlation between species. As is shown
`in Table 3,
`if all signs are predicted to occur in
`man, 53 out of 234 predictions (or 23%) would have
`been correct. Conversely, if none of the signs were
`
`
`
`
`
`Vol. 177, N0- 1
`
`FORECASTING DRUG EFFECTS—-LITCHFIELD
`
`A
`
`f
`
`3?
`
`1na11. This is not the only objective, however, since -
`it is also desirable to maximize tl1e correct predic-
`tions as a per cent of the predictions made. Table 3
`shows that both of these percentages most nearly
`approach simultaneous maxima in the method in
`which the dog is used as thebasis for prediction.
`This is verified by the value of (Chi)2, which is also
`maximal for this method. For the data of this study,
`therefore, the physical signs observed in dogs were
`of the most value in predicting the drug effects in
`man.
`
`Very little has been said about predicting the
`absence of physical signs in man, and this kind of
`prediction merits comment. The results of predic-
`tions may be listed as (1) successful prediction of
`occurrence of a sign in man; (2) failure to predict
`occurrence of a sign in man; (3) successful predic-
`tion of absence of a sign in man;
`(4) failure to
`predict absence of a sign in man. The first outcome
`represents achieving, while the second one repre-
`sents failing to achieve,
`the purpose of toxicity
`studies in animals or,
`in other words, warning or
`failing to warn of a hazard to the patient. The third
`and fourth outcomes are not comparable to the
`first 2. There would seem to be about as much Value
`in predicting correctly that a particular physical
`sign not seen in animals with use of a particular
`drug will not occur in man as there would be in
`predicting correctly that sunrise will not occur at
`
`Table 4.-—-Results of Predictions’?
`
`'
`
`Predictions of Sign
`Occurrence . . . . . . . . .
`.
`.
`. .
`.
`.
`. . . . . . . . . . . . . . . . .
`Absence ................................. . .
`
`Gorract
`29
`11 '
`
`Incorrect Total
`24
`53
`1
`I2
`
`. . .
`. .
`. . . . . . . . . . . . . . . . . . .
`.
`. . . . . . . . . .
`Total
`Per Cent
`. . . . . . . . . .
`. . . . .
`.
`.
`. .
`. . . . . . . . . . . . .
`*(Chi)3 : 6.77, n :: 1, p <0.05.
`
`40
`62
`
`25
`38
`
`65
`I00
`
`midnight tonight. Similarly, failure to make such a
`prediction‘ is equally inconsequential. However, in
`some cases, a drug did produce a physical sign in
`only the rat or dog. In these cases, there is a basis
`for predicting its occurrence or lack of occurrence
`in man. In terms of this study, the most efficient use
`of this information would be to predict that signs
`seen only in rats (and not in dogs) would not occur
`in man, while all signs seen in dogs would be pre-
`dicted to occur in man.
`
`The results obtained on the basis of these pre-
`dictions are shown in Table 4. Although the per
`cent of correct predictions is better than would be
`expected by chance, the reason for this is mainly
`due to the relatively high score achieved in predict-
`ing the absence rather than the presence of physical
`signs.
`Finally, the group of physical signs which were
`noted only in man should be considered. These
`consisted of nasal congestion, localized fat deposi-
`tion, constipation, gastrointestinal irritation and in-
`flammation, aplastic anemia, thrombocytopenic pur-
`
`107
`
`interstitial myocarditis, anuria,
`pura, bradycardia,
`edema, cystitis, vaginitis, trismus, chills, fever, and
`dermatitis. There is no reason to doubt that most of
`these are drug-induced effects. Some of these effects
`can be extremely serious, and animal studies offer
`little hope in predicting most of these effects in man.
`Comment
`
`The purpose of this study was to find a method
`which could be used to examine the hypothesis that
`studies in rats and dogs have predictive value in
`determining the effects of drugs in man. Although
`this is a generally accepted hypothesis, the litera-
`ture discloses no report in which the total spectrum
`of drug eifects of 2 or more drugs tested in animals
`has been examined to establish the extent to which
`their elfects occur in man. An examination of the
`nature of studies in animals as compared to those in
`man immediately discloses certain basic differences.
`In animals, drugs are usually given in intolerable
`doses in order to elicit physical signs of drug action,
`and the reality of any physical sign is judged pri-
`marily by the criterion of dose dependency. In man,
`however, no such practice is or can ordinarily be
`observed. Information obtained from human case
`reports is almost entirely limited to dosage in the
`therapeutic range. Aside from the therapeutic effect,
`all other possible actions of the drug are reported
`as side effects, and a collection of case reports would
`give the incidence of each of these. Excluding symp-
`toms which have no counteipart in speechless ani-
`mals, one might attempt to decide which physical
`signs in man are drug-related on the basis of their
`frequency of occurrence. However,
`this approach
`fails completely because an infrequent physical
`sign from a drug may be entirely reproducible in a
`given patient, while a physical sign that occurs
`frequently may represent no more than it com-
`ponent of the disease or disorder which is being
`treated. Therefore in this study it was necessary to
`adopt the ineflicient assumption that all physical
`signs observed in man were drug-related. Conse-
`quently,
`if the results of this study had failed to
`show that studies in animals have predictive value
`for man,
`it could be argued that this failure was
`due to the crudeness of the approach. On the other
`hand, since this crude qualitative approach demon-
`strated predictive Value of animal studies, one may
`infer that refined quantitative studies would cer-
`tainly verify this conclusion. Although the desired
`result was attained, there is no less need for exam-
`ining the physical signs of drug action in man much
`more critically in order to establish which signs are '
`drug—related and which are not.
`With respect to the animals studied, the dog was
`found to be considerably more useful in predicting
`the drug’s effect in man than was the rat. This is
`consistent with today’s practice of using a third
`species, such as the monkey or chicken, in place of,
`or in addition to, the rat. No data have been pre-
`
`Astrazeneca Ex. 2118 p. 5
`
`
`
`38
`
`DRUG EVALUATION-—-MERLIS AND TURNER
`
`J.A.M.A., July 8, 1961
`
`to establish the general useful-
`sented, however,
`ness of
`these other species compared with the
`rat or dog.
`This study was handicapped by the smallness of
`the sample, namely, only 6 drugs. As a result, the
`initial vocabulary of physical signs generated by
`the 3 species was relatively small. When synony-
`mous or correlated signs were consolidated and’
`those signs which could not occur in all 3 species
`eliminated, only 39 of the approximately 90 origi-
`nally tabulated physical signs remained. A prelimi-
`nary report 2 prior to this study, without a rigorous
`analysis of the data, reached essentially the same
`conclusion, namely, that the predictive value of data
`from studies in laboratory animals could be shown.
`The results of this study should encourage others
`to use this approach on data available to them, and
`to refine it so that more precise and accurate pre-
`dictions can be made. Studies in laboratory animals
`other than the rat or dog should be encouraged in
`the hope that a species may be found which shows
`a better carry-Over of drug effects from animal to
`man.
`
`Summary
`
`The purpose of studies of the safety of new drugs
`in laboratory animals is to obtain forewarning of
`the hazards to man. Although it
`is generally as-
`sumed that these studies have predictive value, this
`has not been demonstrated satisfactorily with re-
`gard to the total spectrum of drug effects seen in
`both laboratory animals and man. A retrospective
`study of 6 drugs which had been investigated ex-
`tensively in the rat, dog, and man was made in
`order to find out if drug eitects showed significant
`correlations among species and, if so, how best to
`utilize this
`information to predict
`from animal
`studies what should be seen in man. Observations
`in dogs were found to be more closely related to
`those in man than were findings in rats.
`References
`
`1. Barnes, ]. M., and Denz, F. A,: Experimciltal Methods
`Used i11 Determining Chronic Toxicity; Critical Review,
`Pharmacol Rev 6:l9l~242 (]une) 1954.
`2. Litchfield,
`]. T., ]r.: Brook Lodge invitational Sym-
`posium on Clinical Drug Evaluation and Human Pharma-
`cology, Clin Plmrmucol 1’: Tlierayi: To be published.
`
`Drug Evaluation and Practical
`Psychiatric Therapeutics
`
`Sidney ]l.’Ier'lis_. M.D.”, and Willicnn J. Turner, M.D., Central Islip, N.Y.
`
`V HE EVALUATION of drugs for use in psychi-
`atry has no true parallel in other fields of medi-
`cine. The preclinical data in this area cannot be
`used to predict reliably the outcome of a thera-
`peutic trial. For the investigator, each new agent
`offers an entirely unexplored possibility. Even the
`methods of exploration are empirical and tentative.
`The differences in therapeutic criteria for the vari-
`ous psychiatric syndromes are such that psycho-
`pharmacological trials must be conducted both on
`hospitalized and nonhospitalized subjects. While
`this is well known, the implications of this fact have
`not been adequately explored. For the psychiatrist
`whose patients are in the hospital, it is possible to
`use more potent agents, and, indeed, this is often
`necessary. However,
`the physician dealing with
`oflice patients must guard against the more marked
`physiological and psychological drug effects,
`for,
`except for brief periods of home care, his patients
`
`From the llesearcli Division and Clinical Facilities of
`Islip State I-lospital.
`
`the Central
`
`The evaluation of psychotropic drugs
`presents special prohlelns to the pharma-
`cologist and clinician. In such evaluation,
`the severity of the patient’s anxiety is a
`u.sel'ul paraineter, but it is not the only
`one that needs to he considered. The best
`therapy may he to learn more about the
`circunlstances of the patient and to re-
`solve difliculties when possible. Drugs
`are prescribed only when this fails. Some
`properties of 25 drugs now used to relieve
`anxiety are given. In severe anxiety, po-
`tent drugs are used initially despite their
`inherent. dangers.
`If an office patient
`drives a car, takes care of a home, cooks,
`watches children, or competes in lJusi-
`ness, paranicters other than anxiety are
`obviously important. The problems of
`psycliopliarinacology are therefore com-
`plex, but
`the principles here outlined
`provide orientation.
`
`108
`
`Astrazeneca Ex. 2118 p. 6