European Journal of
`Clinical Pharmacology
`
`-/
`
`Volume 34, 1988
`
`Managing Editors
`
`J. K.Aronson, Oxford
`H.J. Dengler, Bonn
`L. Dettli, Basel
`F. Follath, Basel
`
`Editorial Board
`
`W.H .Aellig, Basel
`K.-E.Andersson, Lund
`O. M. Bakke, Bergen
`P.J. Barnes, London
`P. R. Bieck, Tubingen
`J. Bircher, Gottingen
`A. Blum , Lausanne
`M. Bogaert, Gent
`A. M. Breckenridge, Liverpool
`H. Breithaupt, Giessen
`F. R. Buhler, Basel
`H. Coper, Berlin
`R. Dahlqvist, Huddinge
`P. Dayer, Genf
`J. F. Dunne, Genf
`M. Eichelbaum, Stuttgart
`J. Elis, Prag
`J. M. Elliott, London
`
`M.Orme, Liverpool
`C. Patrono, Roma
`G. Plewig, Dusseldorf
`R. Preisig, Bern
`L. F. Prescott, Edinburgh
`L. E. Ramsay, Sheffield
`A. Rane, Uppsala
`W. Riess, Basel
`B. E. Roos, Uppsala
`J. M. van Rossum, Nijmegen
`H. W. Seyberth, Heidelberg
`F. Sjoqvist, Huddinge
`J.A.Steiner, Welwyn Garden City
`W. Vetter, Zurich
`S. Vozeh , Basel
`B.Vrhovac,Zagreb
`P. Weidmann , Bern
`L. Werko, Stockholm
`A. Zanchetti, Milano
`G. Zbinden, Zurich
`
`Copy- and
`Language-Editors
`
`A.D .Dayan, Beckenham
`U. Hilgenfeldt, Heidelberg
`
`E. R. Froesch, Zurich
`J. C. Frolich, Hannover
`L. F. Gram, Odense
`H. Greten, Hamburg
`E. Habermann, Giessen
`H. M. von Hattingberg,
`Giessen
`H. Helmchen, Berlin
`E. F. Hvidberg, Copenhagen
`W. H. W.lnman, Southampton
`l.Janku, Prag
`C. R. B.Joyce, Basel
`A. Kaldor, Budapest
`U. Keller, Basel
`A. L. M. Kerremans, Helmond
`U. Klotz, Stuttgart
`M.H. Lader, London
`D. R. Laurence , London
`P. K. M. Lunde , Oslo
`R. Luthy, Zurich
`M.J. Mattila, Helsinki
`U. A. Meyer, Basel
`P. L. Morselli, Paris
`K. J. Netter, Marburg/Lahn
`L. Offerhaus, Amsterdam
`E. E. Ohnhaus t , Kiel
`K. O'Malley, Dublin
`
`t Deceased
`
`~ ~ Springer International
`
`IPR2014-01126- Exhibit 1036 p. 1
`
`

`
`Copyright
`
`Submission of a manuscript implies: that the work described has not been published before (except in the form of an abstract or as part of a published
`lecture, review, or thesis); that it is not under consideration for publication elsewhere; that its publication has been approved by all coauthors, if any, as
`well as by the responsible authorities at the institute where the work has been carried out; that, if and when the manuscript is accepted for publication, the
`authors agree to automatic transfer of the copyright to the publisher; and that the manuscript will not be published elsewhere in any language without the
`consent of the copyright holders.
`
`All articles published in this journal are protected by copyright, which covers the exclusive rights to reproduce and distribute the article (e. g., as offprints),
`as well as all translation rights. No material published in this journal may be reproduced photographically or stored on microfilm, in electronic data bases,
`video disks, etc. , without first obtaining written permission from the publisher.
`The use of general descriptive names, trade names, trademarks, etc., in this publication, even if not specifically identified, does not imply that these names
`are not protected by the relevant laws and regulations.
`
`© Springer-Verlag Berlin Heidelberg 1988
`Springer-Verlag GmbH & Co. KG, 0-1000 Berlin 33
`Printed in Germany by aprinta, Wemding
`
`IPR2014-01126- Exhibit 1036 p. 2
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`

`
`Bur J Clin Pharmacol (1988) 34: 15-19
`
`European Journllli of
`Clinical Pharmacology
`© Springer-Verlag 1988
`
`Dose-Finding Studies in Clinical Drug Development
`
`R Schmidt
`
`Clinical Research Department, SANDOZ Ltd., Basel, Switzerland
`
`Summary. A correct dose-finding study is of the ut(cid:173)
`most importance during clinical development of a
`new drug. It must define the no-effect dose and the
`mean effective and maximal effective doses. Then
`taking tolerability into account, the optimal thera(cid:173)
`peutic dose range can be selected.
`To define the dosage schedule the duration of
`action in man must be tested, if possible together
`with blood concentration measurements. An ade(cid:173)
`quate dose-finding study shows the optimal doses
`for double-blind trials in Phase II and large scale
`trials in Phase III, thereby saving time and effort
`and reducing the number of patients required.
`The tendency of clinical experts to try to demon(cid:173)
`strate superiority of one drug over another by using
`doses higher than patients really need must be re(cid:173)
`sisted. The price paid in poor tolerability exceeds
`any potential benefits.
`
`Key words: dose-finding, drug development; clinical
`trial, therapeutic dose range, proposed procedure,
`dose optimisation
`
`The clinical development of a new drug is usually
`divided into three phases [1, 2]. Phase I is devoted to
`tolerability testing and pharmacokinetic evaluation.
`Trials in late Phase I or early Phase II are aimed at
`elucidating clinical efficacy in the intended patient
`population and to define the dosage and dosage
`schedule. Controlled trials are performed subse(cid:173)
`quently to compare the new drug with the standard
`medications. In Phase III, large scale trials are per(cid:173)
`formed to confirm the efficacy and safety of the
`new drug in the target population.
`Definition of the dosage and dosage schedule is
`a key question during clinical development of a new
`drug, and it is the objective of the so-called dose-
`
`finding studies. The goal is to satisfy the require(cid:173)
`ment that patients be exposed only to the quantity
`of drug that they really need [3]. It is mandatory that
`the therapeutic dose-range be established prior to
`initiation of double-blind studies, in which a fixed
`dosage and dosage schedule are the rule. In spite of
`the crucial importance of dose-finding studies, na(cid:173)
`tional and international guidelines as well as recom(cid:173)
`mendations for clinical drug development at the
`best contain a few general suggestions on how to
`perform such trials. In the following a proposal for
`the procedure is described in more detail.
`
`Selection of Subjects
`
`Whether healthy human volunteers or patients are
`selected depends largely on the indication [4].
`
`Healthy Volunteers
`
`The involvement of healthy volunteers in drug
`studies is officially permitted in most countries and
`is specifically mentioned in the Guidelines laid
`down in the 1975 Tokyo Amendment of the 1964
`"Declaration of Helsinki" [5]. In France the legal
`situation neither prohibits the administration of
`drugs to healthy volunteers nor does it make provi(cid:173)
`sion for it [6].
`Studying healthy volunteers has the following
`advantages [7]:
`
`They are
`1. in a steady-state condition showing
`- no variation due to disease
`- no different stages of disease
`2. easy to recruit
`3. easy to select for age, sex, race, etc.
`
`IPR2014-01126- Exhibit 1036 p. 3
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`16
`
`4. tested under identical conditions (climate, food,
`laboratory values)
`5. not taking concomitant medication
`6. easily prepared to consent in writing
`7. in a condition in which the test can be repeated.
`
`Dose ranging studies can be only performed in
`normal volunteers when there is a reliable test mod(cid:173)
`el with high predictability for the therapeutic effect,
`e. g. prevention of ergometer-induced tachycardia
`for betablockers, prolactin-lowering effect for endo(cid:173)
`crine indications of dopaminergic compounds, his(cid:173)
`tamine flare test for antihistamines, etc.
`The disadvantages of treating healthy volunteers
`are that they cannot receive any potential benefit
`and, in the case of pharmacodynamic studies, that
`they do not show the symptoms of the disease. To
`overcome this shortcoming "symptoms" can be pro(cid:173)
`duced by "provocation tests" [8], e. g. ergometer
`tachycardia. In this way the new substance can be
`tested with regard to whether and to what extent it
`reverses the "provoked" effects in healthy volun(cid:173)
`teers in comparison with placebo and/ or a standard
`drug. Another possibility is to compare the new sub(cid:173)
`stance with a standard drug which itself evokes typi(cid:173)
`cal changes or effects in normals, e. g. the decrease
`in REM sleep evoked by classical antidepressants
`[9]. In such cases the new compound is tested to see
`if it produces the same changes and to compare
`these changes qualitatively and quantitatively with
`the effects of the standard drug. The new substance
`is thus "identified" in terms of changes produced by
`a standard drug, and such tests can be classified as
`"identification tests" [8]. As mentioned above, only
`those test methods should be used whose predicta(cid:173)
`bility for the foreseen disease has been clearly estab(cid:173)
`lished. In addition, the tests must be safe.
`
`Patients
`
`The performance of dose-ranging studies in patients
`IS
`1. mandatory for drug groups for which potentially
`harmful effects may be anticipated, such as cytos(cid:173)
`tatics, immunosuppressants, narcotics etc., and
`2. necessary for drug groups for which there is no
`valid test model in healthy volunteers, e. g. drugs
`for senile dementia, parkinsonism etc.
`
`Indication
`
`In patients the indication should be defined qualita(cid:173)
`tively and quantitatively. Not only the disease for
`which the drug is foreseen must be carefully de-
`
`R.Schmidt: Dose-Finding Studies
`
`fined, but also its gravity and stage. The more in(cid:173)
`novative a drug, the more prepared are the clinical
`expert in the company and the investigator in the
`clinic to select end-stage patients rather than those
`in an early stage of the disease. This may result in
`the recommendation of a too high a dosage for the
`study population in Phases II and III trials. There(cid:173)
`fore the involvement of patients with different but
`well defined stages of the disease is essential in
`dose-finding studies, and interpretation of the re(cid:173)
`sults must take into account the various degrees of
`the disease state.
`
`Study Design
`
`Whether several doses can be tested in the same in(cid:173)
`dividuals (intrapatient comparison) or whether a
`parallel group design, i. e. one dose per group,
`should be chosen depends on the nature of the dis(cid:173)
`ease, and on the condition of the patients. Only
`when the disease is in a steady state is a stepwise in(cid:173)
`crease in dose in the same patient allowed. If the
`disease is expected to show variation over the peri(cid:173)
`od of the trial, a parallel group design is preferable.
`If objective and measurable parameters of the
`disease process can be chosen an open design may
`be sufficient. When subjective symptoms or syn(cid:173)
`dromes must be assessed, treatment must be blind(cid:173)
`ed. In both cases the performance of the study
`should be controlled ("controlled trial").
`
`Definition of the Optimal Dosage
`
`Dose-finding studies should define
`- the no-effect dose range
`-
`the minimum effective dose
`- the mean effective dose
`- the maximum effective dose
`-
`the optimal dose range
`
`The minimum effective dose is the dose which has
`only a borderline effect in a small number of sub(cid:173)
`jects, and the maximum effective dose will produce
`a marked effect in a large proportion of patients.
`Since it is the goal with most developmental drugs
`to produce a greater therapeutic activity and a larg(cid:173)
`er proportion of responders than competitor drugs,
`there is a real risk of choosing a dose that is far
`above the optimal level for use in further studies.
`Another possibility contributing to recommendation
`of too high a therapeutic dose is, as mentioned
`above, the selection of severely disabled or end
`stage patients in early clinical trials. It is essential al-
`
`IPR2014-01126- Exhibit 1036 p. 4
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`

`
`R. schmidt: Dose-Finding Studies
`
`ways to keep in mind the general rule that the high(cid:173)
`er the dose the higher the incidence of side effects.
`As dosage and tolerability are inversely correlated,
`it is of the utmost importance to define the position
`of the "optimal dose range" between the minimal
`and maximal effective doses. Within the optimal
`dose range, the desired therapeutic effect should be
`associated with good tolerability. For a promising
`new drug this means that efficacy and/or tolerabili(cid:173)
`ty will show advantages over competitor drugs, i. e.
`that the new drug is superior. The definite proof of
`any claim of superiority will be provided later in
`the controlled (if possible double-blind) trials in
`Phases II and III.
`During tolerability studies in Phase I, the high(cid:173)
`est well-tolerated dose will have been defined. In
`practice this highest, well-tolerated dose should be
`used as the initial dose in dose-finding studies. If
`this dose has a weak or only a borderline effect, the
`further development of the drug for the selected in(cid:173)
`dication becomes questionable. If the highest well(cid:173)
`tolerated dose produces a clear effect, lower doses,
`e. g. 50% and 25% of it, should be tested in order to
`establish the dose-effect relationship. In addition,
`the dose range must be defined which gives the zero
`value, i. e. which has no therapeutic effect. When(cid:173)
`ever possible a placebo should be included to dem(cid:173)
`onstrate the placebo response, which varies for dif(cid:173)
`ferent indications and populations.
`The correlation between efficacy and tolerability
`is illustrated in Fig. 1.
`Curve Eff shows the increase in efficacy and
`curve Tol the inverse decline in tolerability with in(cid:173)
`creasing dose (d). In the middle, between the "maxi(cid:173)
`mal effective dose" and the "minimal effective
`dose" on curve Eff lies the "mean effective dose".
`The distance between the maximal and minimal ef(cid:173)
`fective doses is the "therapeutic dose range", which
`includes all effective doses. Above the maximal ef(cid:173)
`fective dose lie the supramaximal doses, which do
`not further increase efficacy but only worsen tolera(cid:173)
`bility. Below the minimal effective dose lies the no(cid:173)
`effective dose or placebo range. That is the range
`where effects or side-effects occur which should not
`be attributed to the drug, as they are also observed
`to the same extent and with the same incidence after
`placebo. This is the reason why the effect curve
`starts above the zero point and the tolerability curve
`below the 100% point.
`For some indications the placebo response is re(cid:173)
`markably strong, as in hypertension and analgesia.
`An analgesic produces "effects" at dosages clearly
`below the minimal effective dose. It is important to
`be aware of the differing placebo range for different
`indications and populations [10], and to perform
`
`% Eff.
`
`17
`
`%Tol
`
`o no eff.
`
`max. ft.
`min. eft.
`I
`I
`I
`I
`I
`I
`I
`I~
`: supramax
`:
`I
`I
`' .... __________ ------ -- --- - -- -- - ~I
`ther. dose range
`
`optimal dose range
`
`Interrelation between efficacy (Eft) and tolerability (Tol)
`Fig.1.
`in a dose-finding study. d = dose
`
`dose-finding studies strictly as "controlled trials",
`especially when the placebo range is large.
`Each patient will have an individual optimal
`therapeutic dose. That dose is only valid for that
`patient and not for a study population. For the lat(cid:173)
`ter an optimal dose "range" must be defined, which
`is effective and well tolerated by the majority of re(cid:173)
`sponders. From the two curves in Fig. 1 it is evident
`that it is exceptional for the optimal dose range to
`be centered around the mean effective dose. It lies
`around the point of intersection of the two curves,
`clearly taking into account not only the efficacy but
`also the tolerability curve [11]. If the optimal thera(cid:173)
`peutic dose range is broad, more than one dose
`should be selected for double-blind trials, or it may
`even be necessary to treat patients with indiyidual
`dosages, as is usually the case for psychotropics and
`anti parkinsonism drugs. In order to keep the num(cid:173)
`ber of patients low, as well as for reasons of time
`and capacity, the numbers of doses in comparative
`trials should be as small as possible, and should not
`usually exceed three. Whenever possible a individu(cid:173)
`al dose titration must be avoided.
`
`Duration of Administration
`
`For some compounds (analgesics, diuretics, dop(cid:173)
`aminergics in endocrinology etc.) a single dose or
`single day application will permit definition of the
`optimal dose range as well as the dosage schedule,
`but for other drugs several days or even weeks of
`treatment are necessary, e. g. psychotropics and an(cid:173)
`tiphlogistics.
`
`IPR2014-01126- Exhibit 1036 p. 5
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`

`
`18
`
`Definition of Dosage Schedule
`
`The duration of action should be determined during
`the dose-finding study, as it will allow definition of
`the dosage schedule. Unfortunately, for some sub(cid:173)
`stances (nootropics, immunoactive drugs, etc.) the
`duration of action is difficult to determine during
`early clinical trials, as there is no easily measurable
`and reliable pharmacodynamic parameter. Other
`parameters instead must be taken into considera(cid:173)
`tion, which may suggest a tentative dosage sche(cid:173)
`dule; for example,
`
`1. half-lives in plasma and urine in man and various
`test species
`2. the duration of side-effects or signs of accumula(cid:173)
`tion in the Phase I tolerability tests
`3. receptor binding in vitro, e. g. as for betablockers,
`where a short half-life but high receptor binding
`is likely to lead to a prolonged duration of action.
`4. ph;rmacodynamic data in vivo in animals.
`
`Whenever possible measurement of the duration of
`a pharmacodynamic action in man should lead to
`the definition of the dosage schedule. A study
`planned to define the "plasma concentration-re(cid:173)
`sponse curve" is one of the best means to define the
`duration of action, as it takes into account both the
`duration of action and the pharmacokinetic behav(cid:173)
`iour of the substance.
`
`Blood Concentration-Response Curve
`
`"Pharmacokinetic studies" in healthy volunteers
`and patients and "plasma concentration measure(cid:173)
`ments" during therapeutic trials have different
`goals. Pharmacokinetic studies give information on
`the fate of the administered drug in the organism
`and allow definition of its pharmacokinetic parame(cid:173)
`ters. Plasma concentration measurements in healthy
`volunteers and patients correlate the plasma con(cid:173)
`centration with the quality and quantity of desired
`or undesired effects (therapeutic plasma concentra(cid:173)
`tion monitoring).
`Performing plasma concentration measurements
`during dose-finding studies permits a concentration
`range to be defined within which the desired effects
`or side-effects occur. This will show whether there is
`a correlation between effectiveness and blood level,
`and "whether blood level predicts response" [3].
`A properly designed plan of the timing of blood
`sampling and effect measurements will provide a re(cid:173)
`liable answer about the "blood concentration-re(cid:173)
`sponse curve". A few (about 3-5) blood samples
`
`R. Schmidt: Dose-Finding Studies
`
`drawn during the day will suffice to provide the in(cid:173)
`dividual blood concentration profile. Effect and tol(cid:173)
`erability assessments should be made at the same
`time points to reveal the correlation between blood
`level and activity. Usually, at least the zero (basal)
`value, the maximal concentration (Cmax) and the
`trough level are determined. The results of the ini(cid:173)
`tial pharmacokinetic study must be used to help to
`design this part of the dose-finding studies.
`
`Conclusions
`
`The dose-finding study occupies a key position in
`clinical drug development. If properly designed and
`accurately performed it will save time and effort
`during the comparative and large scale trials of
`Phases II and III, and it will help to minimize the
`numbers of patients required. It must be done early
`during the clinical studies, i. e. at the end of Phase I
`or at the beginning of Phase II. It must include
`measurement of the desired effects as well as side(cid:173)
`effects. For its design and during its practical per(cid:173)
`formance the following notes for guidance should
`be observed :
`
`1. clearly define the study population
`2. select the appropriate patients and avoid includ(cid:173)
`ing only end-stage patients
`3. define:
`3.1. optimal dose range
`include the minimal and maximal effective
`doses as well as the no-effect dose or placebo
`range
`3.2. duration of action and dosage schedule-
`3.3. provisional blood
`concentration-response
`curve
`4. avoid "superior" efficacy if it is due solely to use
`of higher doses than patients need
`5. select one or at the most three doses for compara(cid:173)
`tive trials, and avoid whenever possible individual
`dose titration
`6. confirm tolerability.
`
`References
`
`1. U. S. Department of Health, Education, and Welfare, Public
`Health Service, Food and Drug Administration (1977)
`No.77-3040. General Considerations for the Clinical Evalua(cid:173)
`tion of Drugs. Washington DC 20402
`2. Greenwood DT, Todd AH (1977) From laboratory to clinical
`use. In: Johnson FN and Johnson S (eds) Clinical Trials.
`Blackwell Oxford, London, Edinburgh
`3. Temple R (1982) Government viewpoint of clinical trials.
`Drug Information J 82: 10-17
`
`IPR2014-01126- Exhibit 1036 p. 6
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`

`
`R.Schmidt: Dose-Finding Studies
`
`19
`
`4. Dengler HJ (1973) Early human trials: Selection of investiga(cid:173)
`tors and subjects. In: Clinical pharmacological evaluation in
`drug control. Report on a Symposium, Heidelberg, Nov 72
`WHO (ed). Copenhagen, pp 29 - 36
`5. World Medical Association Inc (1975) Declaration of Helsin(cid:173)
`ki, Tokyo, Japan. Fed Reg 40, p 16056
`6. Arpaillange P, Dion S, Mathe G (1986) Proposals for ethical
`standards in therapeutic trials with humans. Drugs Exp Clin
`Res 12: 11 - 19
`7. Schmidt R (1987) Klinische Pharmakologie in der Pharma(cid:173)
`industrie - Miiglichkeiten und Grenzen. In: Magometsch(cid:173)
`nigg 0
`(ed) Therapieversuch am Menschen. Uhlen-Ver(cid:173)
`lagsgesellschaft, Wien
`8. Schmidt R (1978) Nicht-invasive Methoden in der klinischen
`Pharmakologie. Medita 8: 48-49
`
`9. Spiegel R, Aebi HJ (1983) Effects of psychopharmaceuticals
`on sleep polygrams. In: Psychopharmacology - An introduc(cid:173)
`tion. Wiley, Chichester
`10. Godwey CW (1983) A guide to the pharmacology of place(cid:173)
`bos. Can Med Assoc J 128 : 921 - 925
`11. Simon P, Mery C (1985) Determination de la posologie opti(cid:173)
`mum. In: Pour une meilleure appreciation de la posologie
`optimale des medicaments. Therapie 37: 679 - 687
`
`Received : May 15, 1987
`accepted: June 29, 1987
`
`Dr. R. Schmidt
`SANDOZ Ltd.
`CH-4002 Basel, Switzerland
`
`IPR2014-01126- Exhibit 1036 p. 7