+
`
`THE JOURNAL
`
`I
`
`I
`
`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—HSE‘ISLTIEBI/ILI3VER so
`1961
`
`AMERICAN MEDICAL ASSOCIATION, CHICAGO 10
`
`AstraZeneca Exhibit 2118 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00900
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01913
`
`

`

`34
`
`J.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 Labo—
`ratories, Division of American Cyanamid Company.
`
`Experiments on animals are the most
`important source of data for predicting
`the elfects 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
`or 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 he predicted better from ob-
`servations on dogs than from those on
`rats.
`'
`
`the available evidence along these lines led Barnes
`and Denz,1 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
`
`AstraZeneca Exhibit 2118 p. 2
`
`

`

`
`
`Vol. 177, No. l
`
`FORECASTING DRUG EFFECTS~LITCHFIELD
`
`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 l to 3
`months’, 6 months’ (dogs), and l 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. For‘example, 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 sufficient 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:
`Rat Dog Man
`.
`Impaired reflexes, hypotension, ataxia,
`decreased activity .................................... +"‘ +
`+
`Weight loss ............. . .............................. +
`+
`at
`Tremors ................................................
`..
`+
`+
`Ptosis, urinary incontinence, catatonia ............. +
`..
`..
`Lacrimation ............................................
`..
`+
`..
`
`Diarrhea ................................................
`..
`..
`+
`i+=occurrence
`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 ditterent 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 rats and man but not dog.r
`Rat, man
`Sign elicited in both dogs and man but not rat
`Dog, man
`Rat, dog, man 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 (Chili as
`g (observed—expected) 2.
`expected
`
`Results
`
`When 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 201‘ 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.
`The objective of this tabulation is to contrast
`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)2 value permits the
`inference that a correlation is present between the
`
`AstraZeneca Exhibit 2118 p. 3
`
`

`

`36
`
`FORECASTING DRUG EFFECTS—LITCHFIELD
`
`].A.M.A., July 8, 1961
`
`different species. The (Chif of 43.5 is significant,
`and results from the fact that
`the observed fre«
`quencies were quite diHerent in several cases from
`the expected value, which is calculated on the
`assumption that all classes are alike in relative
`frequency.
`[(Chi)2 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 carrynover of physi-
`
`Table 1.—Occurrence of 39 Physical Signs from
`Six Drugs in Three Species
`
`
`
`i
`
`. ..
`...
`1
`
`1
`
`. ..
`
`1
`
`. . .
`.. .
`
`. .
`
`1
`.
`1
`2
`1
`...
`2
`
`1
`
`1
`
`1
`1
`1
`1
`1
`. .
`
`.
`
`1
`
`1
`1
`2
`. . .
`.
`
`3
`1
`. . .
`
`1
`
`...
`. ..
`
`. ..
`
`4
`
`1
`1
`..
`‘2
`
`1
`1
`2
`
`'
`
`...
`...
`
`...
`1
`
`1
`
`1
`
`1
`2
`. ..
`1
`
`1
`
`1
`1
`1
`
`l
`
`. .
`..
`
`. ..
`...
`1
`1
`
`1
`1
`2
`
`..
`1
`
`1
`
`...
`1
`
`. . .
`
`...
`1
`
`. ..
`
`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
`(Obs.—
`
`,—-————d\—~————\ Exp.)2 ,————-—~A—————~—s Exp.)"’-
`Class
`Observed
`Exp.
`Class
`Observed
`Exp.
`Absent
`146
`17
`Man
`23
`5.9
`Rat
`11
`0.4
`Rat, man
`1
`1.3
`Dog:
`16
`1.0
`Dog, man
`12
`(LO
`Rat, dog
`8
`6.1
`Rat. dog
`17
`20.2
`and man
`
`Total
`Observed
`16!!
`12
`28
`25
`
`iu.l
`[8|
`Totals
`* (Chi): : 43.5, n : 3, D <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. 1n 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 com~
`bined to give a total of 19 for the “rat” class. The
`values for the “man” column are obtained in a
`similar manner. When 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
`
`Rat.
`Rat Dog Dog.
`Rat
`and and and
`and
`Ab-
`sent Rat Dog Dog Man Man Man ‘M an
`Physical Signs
`Weightloss ..................
`2
`4
`
`height gain .........
`3
`
`Muscle atrophy .......
`4
`
`Myositis ...........
`5
`
`Lympliocytopenia
`4
`Neutropenia .........
`5
`
`Leukopcnia ..........
`3
`
`Anemia ..............
`.. .
`1
`Leukocytosis .............
`3
`Hyperglycemia ...........
`5
`...
`Liver damage ........
`2
`
`Jaundicc ..................
`5
`Fatty liver
`..
`5
`Polydipsia
`6
`Polyuria ..
`2
`Oliguria ..................
`4
`Hematuria ...............
`3
`Crystallurin or renal
`concretions .............
`5
`Renal damage ............
`3
`Gastroduodenal ulcer
`.. .
`.
`4
`Diarrhea ..................
`1
`.....
`Salivation ..
`5
`
`Ataxia ................
`'2
`
`Impaired reflexes .........
`3
`Decreased activity .
`3
`
`. ..
`Tremors ........
`3
`
`Ptosis ....................
`5
`Catatonia ................
`5
`.. .
`Priapism ......
`5
`
`Lacrimation ..............
`5
`Urinary incontinence .....
`4
`Bacterial invasion ........
`5
`Parasitic invasion ........
`4
`Decreased thyroid
`iunction ................
`Genital hypoplasia .......
`Decreased adrenal function
`(cortical) ...............
`Hypotension ........
`Lung edema ........
`Tachypnea .........
`Totals ..............
`
`. ..
`1
`1
`1
`...
`1
`
`...
`
`2
`
`1
`
`l I
`
`4
`4
`
`5
`2
`5
`5
`146
`
`
`
`..
`
`1
`
`...
`
`. ..
`
`...
`
`.1
`
`...
`2
`
`8
`
`23
`
`I
`
`..
`1
`Hi
`
`1
`1
`
`1
`
`[2
`
`1
`
`1
`1
`
`l7
`
`cal signs from animals to man. Altogether, 5 differ-
`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, 58 out of 234 predictions (or 23%) would have
`been correct. Conversely, if none of the signs were
`
`Table 3.—Results of Five Different Methods of Predicting
`Occurrence of Physical Signs in Man
`Correct
`Predictions
`as % of Total
`r——~—J»——\
`Predic-
`Incidence
`tions
`in Man Made
`.. .
`'23
`
`Glass
`Not
`Class Man Man
`181
`Total
`:33
`
`(Chl)2
`
`16-2
`Not rat
`19
`Rat
`13?
`Not dog
`24
`Dog
`Not rat
`and dog 173
`Rat and
`Clog
`8
`Not. rat ,
`1.16
`or dog,r
`Rat or
`dog
`
`35
`
`35
`18
`24
`'29
`36
`17
`28
`
`3O
`
`31
`
`55
`
`32
`
`57
`
`49
`
`55
`
`68
`
`4G
`
`19
`
`40
`
`30
`
`27
`
`Predlct 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
`
`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 Exhibit 2118 p. 4
`
`

`

`
`
`Vol. 177, N0. 1
`
`FORECASTING DRUG EFFECTS~LITCHFIELD
`
`I
`
`l
`
`37
`
`man. This is not the only objective, however, since -
`it is also desirable to maximize the 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 the'basis 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 (I) 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’l‘
`
`I
`
`Predictions of Slgn
`Occurrence ................................
`Absence ...................................
`
`Correct
`29
`11 '
`
`Incorrect Total
`24
`53
`1
`I2
`
`Total ...................................
`
`Per Cent ................................
`*(Cbifi : 6.77, n : 1, p (0.05.
`
`40
`62
`
`25
`38
`
`65
`lot)
`
`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 drugainduced 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 effects of 2 or more drugs tested in animals
`has been examined to establish the extent to which
`their effects 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 counterpart 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 a com-
`ponent of the disease or disorder which is being
`treated. Therefore in this study it was necessary to
`adopt the ineflicient as5umption 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 Exhibit 2118 p. 5
`
`

`

`38
`
`DRUG EVALUATIONwMERLIS 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 effects 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, J. M., and Denz, F. A.: Experimental Methods
`Used in Determining Chronic Toxicity; Critical Review,
`Pharmacol Rev 6:191~242 (June) 1954.
`2. Litehfield, J. T., In: Brook Lodge invitational Sym-
`pOsium on Clinical Drug Evaluation and Human Pharma-
`cology, Clin Pharmacol d7 Therm): To be published.
`
`Drug Evaluation and Practical
`Psychiatric Therapeutics
`
`Sidney Mm-lis, M.D.‘, and William ]. 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. “7liile
`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
`office patients must guard against the more marked
`physiological and psychological drug effects, for,
`except for brief periods of home care, his patients
`
`From the Research Division and Clinical Facilities of the Central
`Islip State Hospital.
`
`The evaluation of psychotropic drugs
`presents special problems to the pharma-
`cologist and clinician. In such evaluation,
`the severity of the patient’s anxiety is a
`useful parameter, but it is not the only
`one that needs to be considered. The best
`therapy may be to learn more about the
`circumstances of the patient and to re-
`solve difficulties 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 busi-
`ness. parameters other than anxiety are
`obviously important. The problems of
`psychopharmacology are therefore com-
`plex, but
`the principles here outlined
`provide orientation.
`
`108
`
`AstraZeneca Exhibit 2118 p. 6
`
`