urope n 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
`0. M. Bakke, Bergen
`P.J. Barnes, London
`P.R. Bieck, Tubingen
`J. Bircher, G6ttingen
`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. Patrone, Roma
`G. Plewig, Dusse1dorf
`R. Preistg, 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
`8. Vrhovac, Zagreb
`P. Weidmann, Bern
`L. Werko, Stockholm
`A. Zanchetti, Milano
`G. Zbinden, Zurich
`
`Copy- and
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`
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`
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`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. Inman, 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
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`K. O'Malley, Dublin
`
`t Deceased
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`© Springer' Verlag Berlin Heidelberg 1988
`Springer-Vedag dtribH & Co. KG, b-1 Mt)· Bedin 33
`Printed In Getmany by .apl'inta, Wemdi 11g
`
`

`
`Eur J Clin Pharmacol (1988) 34: 15--19
`
`European Journal 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 Il 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 pharrnacokinetic 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
`perfonn 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.
`
`

`
`16
`
`R. Schmidt: Dose-Finding Studies
`
`:I
`:1
`
`~:i
`·-:(.S-
`
`4, tested under identical conditions (climate, food,
`laboratory values)
`5 .. not taking concomitant medication
`6. easily prepared to consent in writing
`7. irt a condition irt 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 pred.ictability for the therapeutic effect,
`e.g. prevention of ergometer~induced tachycardia
`for betablockers, prolactin,Ioweri:ng effect for endo'(cid:173)
`crine indications of dopaminergic compounds, his·
`famine flare test for antihistamines; etc.
`The disadvantages of tteatirtg 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. ln 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 ill eomparlsoli with placebo and/ or a standard
`drug. Another possibility is to compare the ti:e\V sub(cid:173)
`.stance With a standatd drug which itself evokes typi(cid:173)
`cal changes or effects fo. normals; e. g, the decrease
`in REM sleep evoked by classical antidepressants
`[9J. 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 ofchange,S: produced by
`a standard drug; a11d such tests can he classified as
`"identification tests" [8]. As n1eritioned above, only
`those test methods should be used whose predicta(cid:173)
`bility. for the foreseen disease has been clearly estab~
`lished. In addition, the tests must' be safe.
`
`Patients
`The penorma11ce of dose~ranging studies in pa ti ent.5
`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 quafita(cid:173)
`tive1y and quantit-atively. Not only the diSease for
`which the (!tug is foreseert must be carefully de-
`
`'\!cl:
`.i~
`
`!~ .J
`
`A I
`
`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 t-0 select e11d-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 Ill trials. There~ j
`fore the involvement of path~rtts with different but
`well defined stages of the disease is. essential in
`dose-finding studies, and interpretation of the re~
`suJts must take into account the various degrees of
`the disease state.
`
`f
`:'
`
`Study Design
`
`Whether several doses can be tested in the same in•
`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·
`crease in dose in the same patient allowed. If the
`disease is expected to show variation over the pen·
`od of the trial, a parallel gl'oilp design is preferable.
`It objective and measurable para.meters 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 cortttolled ("controlled trial'').
`
`Definition of the Optllnal 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 mirtimmi1 effective dose is the dose which has
`only a borderline effect in a sma11 iiumber of sub,
`jects, and the maximum effective dose will produce
`a marked effect in a large proportion of patient<;.
`Since it is the goal with most developmental drugs
`to pl'oduce a greater therapeutic activity a:n<l a larg~
`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-
`
`

`
`: .,.
`
`::.R.;$chmidt: Dose-Finding.Studie·s
`
`17
`
`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 mlnimal
`and maximal effective doses, Within the optimal
`dose range; the desired therapeutic effect should be
`associated with good tolerability. For a proinising
`new drug this meat1s tMt 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
`arty claim of superiority will be provided later in
`the controlled (if possible double-blind) trials in
`Phases 11 and UL
`During tolerability studies in Phase L 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. lf
`this dose has a weak or only a borderl.ine effect, the
`further development of the drug for the selected in~
`dication becomes questionable, If the highest well(cid:173)
`tolerated dose produces a clear effect; lower doses,
`e, g~ 50% and 25% of it, sht)uld be tested in order to
`est<J,blish the dose-effect relationship. In addition,
`the dose range rri.ust be defined which gives the zero
`value, Le. which has no therapeutic effect. When(cid:173)
`ever possible a placebo should he included to dem(cid:173)
`onstrate the placebo respo11se, which varies for dif~
`ferent indications and populations.
`1lie correlation between efficacy and tolerability
`is illustrated in Fig. 1,
`·
`C11rve Eff shows the increase in efficacy and
`curve Tol the inverse dedhie in tolerability with in(cid:173)
`creasing dose ( d)c lnthe middle, betweei1 the "ma.xi(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 au .effective doses. Above the maximal .ef(cid:173)
`fective dose lie the sitptamaxintal dos.es, which do
`not further increase efficacy but ohly worsen tolera(cid:173)
`bility. Below the ininimal 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 incide11.ce after
`placebo. This is the reason why the effect curve
`starts above the zero point and the tolerability c11rve
`below the 100% point,
`For some indications the placebo response is ie(cid:173)
`markahly strong, as in hypertension ari<l anaigesfa.
`An analgesic produces "effects;; at dosages clearly
`below the minimal effective dose. It is important to
`be aware ofthe, d1ffenng placebo range for different
`indications and populations [1Q], and to perfo:rm
`
`I
`I
`
`' I
`
`I
`I
`I
`
`ti
`:
`-£
`,----r· -·-+---+---T--·-·······----·--iC---'-'-+
`rn·ax:.:.eN,
`u
`no efL
`·min. eff.
`mean -eff.
`d
`!
`·1
`!+----+
`~PtHTial.dOs.e range
`~sUprarnax
`1
`I
`I
`·t....·--;..:.:..--:...-:-----.c.--:---···-.----···--)•J
`ther:.-dOse.·range
`
`l
`
`j
`
`Interrelation between efficacy (Eff) and tolet'lJ;bility (Toi)
`E'ig.1.
`in a dose.-finding.study; a.-.dose
`
`dose-finding stttdies strictly as "controlled trials'\
`especially when the placebo rati,ge is large.
`Each patient will have an h1dividual 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 he defined, which
`is effective and well tolerated by the majority of re~
`sponders. From the two curves b1 Fig.1 it.is evident
`that it is exceptio11al for the optimal dose range to
`be centered around the mean effective dose. It lies
`around the point of fotel'settion of the two cutves;
`cleal'ly taking iilto account not only the efficacy but
`also the tolerability curve [HJ. 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
`antiparkinsonistn drugs. In order to. keep the num(cid:173)
`ber of patients low, as well .as for .reasons of tilne
`atJ:d capacity; the numbers .of doses in comparative
`trials should he as small as possible;. and should not
`usually exceed three, Whenevei· possible a individu(cid:173)
`al dose titration must be avoided.
`
`Duration of Administration
`
`For some compounds (analgesics, diure1tics, dopw
`aminetgks fo endocrinology etc.) a single dose or
`single day application will permit defh1ition 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.
`
`

`
`18
`
`Definition of Dosage Schedule
`
`'fhe duration .of action should be determined during
`the dose-finding study, as it will allow definition of
`the dosage schedµle. Unfortunately, for some sub(cid:173)
`st;:tnQes (noottopics, immunoactive drµgs, etc,) the
`durati():n of action is difficult to detet111~ne during
`early clinical trials, a:s there. is no easily measurable
`and reliable pharmaeodynamic parameter. Other
`parameters instead must be taken into considera·
`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 dµrati()n of side~eff ects or signs of accumula(cid:173)
`tion ln the Phase 1 toleral:>ility tests
`3. receptor binding in vitro, e.g. as for betabl-Ockers,
`where. ii .. short half-life hiit high receptor binding
`is likelyto lead to a prolonged duration of acfron.
`"'
`4. phannacodynamic data in vivo in animals.
`
`.
`
`Whenever possible measurement of the duration of
`a phannacodynamic action in man should lead to
`the dethlmon of the dosage schedule. A study
`plmrned to c:iet111e the "plasma concentration-re(cid:173)
`sponse curve" is one of the best means to deffoe the
`dt1tation 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 bea:lt1ty volutrteers
`and patients and "plasma concentration measure"
`inents" during therapeutic: trials have different
`go::1ls. Pharmaookinetic studies give information on
`the fate. of the administered drug .in the organism
`and a:llow .defmition ofJts pham1acokinetic parame~
`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 effeQts (therapeutic; plasma concentra(cid:173)
`tion monitoring)~
`Perfol1rlip:g plasma concentration measu.retnents
`during dose-finding studies pennits a concentration
`ram~e to be defined within which the desired effects
`ot side-effects occur. This will show whether there is
`a correlation between effectiveness and blood level,
`artd "whether blood Jeyel predicts response" 13].
`A pro petty dt:Jsigned plan of the tii.ning of blood
`'SB.IIlPling an cf effect meas11rements will pr() vi de a re(cid:173)
`liable answer about the "blood concentratio11~re­
`sponse cµrve" .. A few (about 3~.5) blood samples
`
`RScllmidt: Dosc~Finding Studi~
`
`drawn during the day wiU suffice. to provide the in~
`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 {CmaJ and the
`trough level are detetmi1wcl, The results of the ini(cid:173)
`tial p}1artnacokfuetio study 111ust 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. lfproperly designed and
`acc1)rfl;tely petfon11ep it will save time and effort
`diiring the compan1tive and large sc;:tle trials of
`Phases JI and III, and it will he:lp to minini,ize t1Ie
`numbers of patients required. It must be <:!'one. eatly
`during the clinical stJ.1diesi i.e. at the end of Phase I
`or at the beginning of PhaseTI. It must include
`measurement of the desired effects as well as side~
`effects, For its design and during its practical per(cid:173)
`fonnance the following notes for guidance should
`be observed:
`·
`
`1. <:1learly define the study po;pulation
`2.select the appropriate patients and avoid in.dud.
`ing ouly end-stage patients
`3. define:
`3J. optimal dose range
`include the minimal and maximal effective
`doses as well as the noceffect dose or placebo
`range
`,3.2. duration of acction an4 dosage sched.ule- ·
`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•
`tive trials, and avoid whenever possible individual
`dose titration
`6. confirm tolerability.
`
`References
`
`1. U.S. Departrrient of He:altb, Educii.tio.11, and Welfare, Pµblic
`Health Serviee, Food and Drug Adrninistratio.n (1977)
`No. 77·3040. General Con$icl¢rations for .the. Clinical Evalua(cid:173)
`tion of l):rugs. Wllshington DC20402
`.z. Greenwood DT, Tod<i AH ('1977) From laboratory to clinical
`u~e. lil: Johnson .FN and .Jo~on S (eds) Clinical Trial.$.
`Bll!Ck.well Oxford, Lonqon., Editiburgh
`3. Temple R {l98:D Qovern111ent viewp,oinJ of cli.nical trials;
`Dn.1g Information J 82: l().'-.17
`
`

`
`pengle.t HJ {1973) Eady human tria1s: Selection ofinvestlga(cid:173)
`tors and subjects. In: Clinical pharmacological evaluation in
`dt1lg 6Qi1lrot Report on a Symposium, Heidelberg, Nov 12
`WHO (ed). Copenhagen, pp 29<36
`5, World Medical Association Inc (1975) Declaratio11 of Helsin(cid:173)
`ki, Tok.yo, Japan. Fed Reg 40. p 1605.6
`6. Arpailli\11ge P, Dion S, Mathe G (19&6) Proposals for ethical
`standards in therapeutic trials. With. humans. Drugs. Exp Clin
`Res 12; rt-19
`1. Sch!Tlidt R (1987) Kllmsche .Phatmako1Pgie 1ri det PhA.nnl)•
`hidustrie - Moglfohkeiten titld Grenzeh. Ih: Ma~ometsch­
`nigg D (ed) Thetapieversuch am Menschen. Uhle1t-Yer-
`lagsgesellschaft, Wien
`.
`..
`8. Schmidt R (197&) Nichtcinvasive Methoden hi det klinischei1
`. J?Jlarrnakologie. Medita 8: 48"49
`
`19
`
`9. SpiegeLR, Aebi HJ {1983) Effects of psychopharn1aceutieals
`on sleep polygrams. In: Psychopharmacology - Art introduc-
`·
`tion. Wiley, Chichester
`1-0. Godwey CW (1<183) A guide. to the pharmacology of place(cid:173)
`bos. Can MEid Assoc J 128: 921-925
`11. Simon P, Mery C (19.85) Detetrninatiort de fa posologie opti(cid:173)
`mum. fo:. Pour une meilleure ap,iJreciatiOrt de la pqi;9lqgie
`optimale<les medicaments, Therapie 37: 679-687
`
`Received: May 15, 1987
`accepted: June 29, 1987
`
`Dr. RSchmidt
`SANDOZ Ltd.
`CH -4002 Basel, Switzel'land