`
`55972 Federal Register I Vol. 59. No. 216 it Wednesday November 9. 1994 i' Notices
`
`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
`
`F005 and Drug Administration
`[Docket No. 93041“!
`
`International Conference on
`Harmonlsatlon: Dose-Response
`Information to Support Drug
`Registration: Guideline: Availability
`
`sponsors. The guideline describes the
`been undertaken by regulatory
`value and uses of dose-response
`authorities and Industry assoctations to
`information and the kinds of studies
`promote international harmonization of
`that can obtain such information. and
`regulatory requirements. FDA has
`gives specific guidance to manufacturers
`participated in many meetings deSigned
`on the kinds of information they should
`to enhance harmonization and is
`obtain.
`committed to seeking sctentifically
`In the past, gutdelinas have generally
`based harmonized technical procedures
`for pharmaceutical development. One of been issued under § 10.90[b] (21 CFR
`the goals of harmonization is to identify
`10.9mm]. which protrides for the use of
`and then reduce differences in technical guidelines to state procedures or
`r utremerits for drug development.
`standards of general applicability that
`AGENCY: Food and Drug Administration.
`CH was organized to provide an
`are not legal requirements but that are
`HHS.
`opportunity for harmonization
`acceptable to FDA, The agency 15 now
`ACTION: Notice.
`———-—»-————-————— initiatives to be developed with input
`in the process of revising § 10.9003).
`SUMMARY‘ The Food and Drug
`from both regulatory and industry
`Therefore. the guideline is not being
`Administration {FDA} is publishing a
`representatives. FDA also seeks input
`issued under the authority of current
`final guideline entitled "Dose-Response
`from streamer-representatives and
`5 mouth]. and it does not create or
`information To Support Drug
`others. 181-! is concerned with
`confer any rights. pmrgleggs, or benefits
`Registration." The guideline is
`harmonization of technical
`for or on any person. nor does it Operate
`applicable to both drugs and biological
`requirements for the registration of
`to bmd F'DA m any way.
`products. This guideline wasprepared
`pharmaceutical products among three
`As with all of FDA‘s gurdelines. the
`y the Efficacy Expert Working Group of
`regions: The European Union. Japan.
`public is encouraged to submit written
`the International Conference on
`and the United States. The Six ICH
`comments With new data or other new
`Harmonisation 0f “3011111331
`sponsors are the European Commisston.
`information pertinent to this guideline.
`Requirements for Registration or
`the Emnaan Federation Of
`The comments in the docket will be
`Pharmaceuticals for Human Use (lCH).
`Pharmaceutical Industry Assoctations.
`periodically renewed. and where
`The guideline describes why dose-
`the Japanese Ministry Of Health 311d
`appro mate. the guideline will be
`response information is useful and how Welfare. the Japanese Pharmaceutical
`amen ed. The public will be notified"of
`it should be obtained in the course of
`Manufacturers Assocmtion. FDA. and
`any such amendments through a notice
`drug development. This information can the US. Pharmaceutical Research and
`m the Federal Register.
`help identify an appropriate starting
`MfinUfflCturfim 0f Amenca. The ICH
`Interested persons may at any time,
`dose as well as how to adjust dosage to
`5303:3391. Whmh coordinates the
`submit written comments on the
`the needs ofa particular patient. It can
`preparation of documentation. is
`guideline to the Dockets Management
`also Identify the maximum (1105888
`PIT-""1919“i by the Interoatronal
`Branch [address above]. Two copies of
`beyond which any added benefits to the
`Federation 0‘ thaCBl-itical
`any comments are to be submitted.
`patient would be unlikely or would
`Manufacturers Associations “PPMM-
`except the indiiriduals may submit one
`produce unacceptable Side effects. This
`That [CH {Steering Committee includes
`copy. Comments are to be identified
`guideline is intended to help ensure that
`representatives from “Ch 0f ”'19 ICH
`with the docket number found in
`dose response information to support
`5130115013 and IFPMA- *3 well 55
`brackets m the heading of this
`drug registration is generated according
`observers from the World Health
`document. The guideline and received
`to sound “lentil.“ principles.
`Organisation. the Canadian Health
`comments may be seen in the office
`EFFECTIVE DNI'E: November 9. 1994.
`Erote'ptirzin mob. and the European
`above between 9 am. and 4 pm,
`ADDRESSES: Submit written comments
`rial 31:13:th held on March 8 9 and Monday ”“0“
`Friday.
`_
`on the guideline to the Dockets
`10' 1993. the [CI-I Steering Committee
`The text of
`a final guideline follows:
`Management Branch [HFA-BUS], FUOd
`agreed that the draft tripartite guideline Dow'MPI-‘tm Information ‘0 SHPPBH ”ms
`and Drug Administration, 12420
`entitled “Does-Response Information To ”Emmi“
`Parklewn Dr.. rm. 1'23! Rockville. MD
`Support Drug Registration" should be
`1 Introduction
`2035? Copies of the guideline are
`made available for comment. [The
`'
`available [mm the CDER Executive
`document 15 the product of the Efficacy
`Purpose ofDoss-Response Information
`Secretariat Staff (HFD—B]. Center for
`Export Working Group of ICH.)
`Knowledge of the-relationships among
`Drug Evaluation and Research. Food
`Subsequently the draft guideline was
`dose. drug concentration In blood. and
`and 131113 Admtnistration. 750" Stafl‘mh made available for comment by the
`cum“ "Span“ (”Hecuveness and
`PL, Rockville. MD 20355.
`European Union. and Japan. as well as
`ungesipable effects: as important-lilo:1Ll}? safe
`F0“ ”WE“ WWW?" mm“
`by FDA {see 56 FR 37402. July 9. 19931. Ellifail-tillfiifimfiiifll‘tlfl flimsy
`_
`3383“de the guideline: R0139“
`in accordance with their consultation
`3,, appmpnm signing dose. the best we). in
`Temple, Center for Drug Evaluation
`procedures. The comments were
`adiust dosage to the needs of a particular
`311d RBSBETCh {HFD‘400L FDDd 811d
`analyzed and the guideline was reused
`patient. and a dose beyond which increases
`Drug Administration, 5500 Fishers
`as necessary. At a meeting held on
`would be unlikely to provtde added benefit
`Lane. Rockville, MD 20857 301-
`March 10_ 1994. the [CH Steering
`or would produce unacceptable aide effects.
`4.43.4339
`Committee agreed that this final
`Dose-concentration. concentratiom andi'or
`Regarding ICH: Ianet Showelter.
`Billdfiline should he uhlished.
`dose-response information is used to piepare
`0mm of Health Affairs (Her-i).
`With this notice.
`A is publishing a We and swimmers meme?“ in
`Food and Drug Adininistration.
`final guideline entitled "Dose-Response
`product labeling. In addition. know edge of
`.
`.
`use-response may provtde an economical
`5800 Fishers lane. RockVille. MD
`Information To Support Drug
`approach to global drug development. by
`20857 301—443-1381
`Registration." It ”5 applicable to both
`enabling multiple regulatory agencms to
`SUPPLEMENTARY INFORMATION: In recent
`drugs and biological products. This
`make approval declstons from a common
`years, many important initiatives have
`guideline has been endcrsed by all ICE-l
`database.
`
`ATI 1014-0001
`
`ATI V. ICOS
`
`IPR2018-01183
`
`ATI 1014-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`

`

`55973
`Federal Register l Vol. 59. No. 216 l Wednesday November 9. 1994 I Notices
`
`Historically. drugs have often been Initially
`marketed at what were later recognised as
`excessive doses {i.e.. doses well onto the
`plateau of the dose-response curve for the
`desired effect]. sometimes with adverse
`consequences [e.g.. hypoltalemia and other
`metabolic disturbances with Ebrszide-t'y'pe
`diuretics in hypertension]. This situation has
`been improved by attempts to find the
`smallest dose with e discamible useful effect
`or e maxtrnurn dose beyond which no further
`benefiCial effect is seen. but practical study
`designs do not eitist to allow for precise
`determination of these doses. Further.
`expanding knowledge indicates that the
`concepts ofminunuln effective dose and
`maxtmum useful dose do not adequately
`account for indivtdual differences and do not
`allow a comparison. at venous doses. of both
`benefictal and undesirable effects. Any given
`dose provides a mixture of desirable and
`undesirable effects. with no single dose
`necessarily optimal for all patients.
`Use of Dosefiesponse lnfonnoo'ori in
`Ch nosing Doses
`What is most helpful in choosing the
`starting dose of a drug is knowing the shape
`and location of the population {group}
`average dose-response curve for both
`desirable and undesirable effects. Selection
`of dose is best based on that Information.
`together with a ludgrnent about the relative
`importance of desirable and undesirable
`effects. For example. a relatively high starting
`dose [on or near the plateau of the
`effectiveness doeevresponse curve) might be
`recommended for a drug with a large
`demonstrated separation between its useful
`and undesirable dose ranges or where a
`rapidly evolvtng disease process demands
`rapid effective intervention. A high starting
`dose. however. might be a poor choice for a
`drug with a small demonstrated separation
`between its useful and undesirable dose
`ranges. In these cases. the recommended
`starting dose might best be a lowr dose
`exhibiting a clinimlly important effect in
`even a fraction of the patient population.
`with the intent to titrate the dose upwards as
`long as the drug is well tolerated. Choice of
`a starting dose might also be affected by
`potential intersub1ect variability in
`pharmacodynarmc response to a given blood
`concentration level. or by anticipated
`intersubiect pharrnecoktnetic differences.
`sud: as could arise from nonlinear kinetics.
`metabolic polymorphism, or a high potential
`for phannecokinetic drug-drug interactions.
`In these cases. a lower starting dose would
`protect patients who obtain higher blood
`concentrations. It is entirely possible that
`different physicians and even different
`regulatory authorities. looking at the same
`data. would make different choices as to the
`eppropnate starting doses. dose-titration
`steps, and maximum recommended dose,
`based on different perceptions of rislu'beriefit
`relationships. Valid dose raspOnse data allow
`the use of such Judgment.
`[ii adjusting the dose in an individual
`patient after observtng the response to an
`initial does. what would be most helpful is
`knowledge of the shape of indivtdual dose-
`response curves. which is usually not the
`same as the population {group} average dose-
`
`response curve. Study designs that allow
`estimation of individual dose-response
`curves could therefore be useful in gutding
`titration. although experience with such
`designs and their analysis is very limited.
`In utilizing dose-response information. it is
`important to identify. to the extent possible.
`factors that lead to differences in
`phen'nacokinetics of drugs among
`Inditriduals. including demographic factors
`[e.g.. age. gender. race}. other diseases [e.g..
`renal or hepatic failure). diet. concurrent
`therapies. or individual characteristics [a.g..
`weight. body habitus. other drugs. metabolic
`differences).
`
`Uses ofConceiitmti'on-Recporise Data
`Where a drug can be safely and effectively
`given only with blood concentration
`monitoring, the value of concentratiom
`response information is obvious. In other
`cases. an established concentration-response
`relationship is often not needed. but may be
`useful: [1] For ascertaining the magnitude of
`the clinical consequences of pharmacokinetic
`differences. such as those due to drug-disease
`[e.g. renal failure) or drug-drug interactions:
`or [2} for assessing the affects of the altered
`phanriacoltinetics of new dosage forms [e.g..
`controlled release fomiulation] or new
`dosage regimens without need for additional
`clinical trial data. where such assessment is
`permitted by regional regulations.
`Prospective randomtzed concentration-
`response studies are obviously critical to
`defining concentration monitoring
`therapeutic "windows. but are also useful
`when pharmacoktnetic variability among
`patients is great; in that case. a concentration-
`response relationship may in principle be
`discerned in a prospective study with a
`smaller number of sub1ects than could the
`dose-response relationship in a standard
`dose-response study. Note that collection of
`concentration-response information does not
`imply that therapeutic blood level
`monitoring will be needed to administer the
`drug properly. Concentratiowresponse
`relationships can be translated into dose-
`response information. Concentration-
`rosponse information can also allow selection
`of doses (based on the range of
`concentrations they will achieve) most likely
`to lead to a satisfactory response.
`Alternatively, if the relationships between
`concentration and observed effects [e.g.. an
`undesu-able or desirable pharmacologtc
`effect] are defined. the drug can be titrated
`according to patient response without the
`need for further blood level monitoring.
`Problems With Titration Demgns
`A study destgn Widely used to demonstrate
`effectiveness utilizes dose titration to some
`effectiveness or safety endpoint. Such
`titration designs. without careful analysts. are
`usually not informative about doseresponse
`relationships. In many studies. there is a
`tendency to spontaneous improvement over
`time that is not easily distinguishable from
`an increased response to higher doses or
`cumulative drug exposure. This leads to a
`tendency to choose. as a recommended dose.
`the highest dose used in such studies that
`was reasonably well tolerated. Historically.
`this approach has often led to a dose that was
`
`well in excess of what was really necessary.
`resulting in increased undesrrable effects.
`eg. to high-dose diuretics used for
`hypertension. In some cases. notably where
`an early answer is essential. the titration-to-
`highest-tolerable-dose approach is
`acceptable. because it ofien requires a
`minimum number of patients. For example.
`the first marketing of zidotrudine (AZT) for
`treatment of people with acquired immune
`deficiency syndrome [AIDS] was based on
`studies at a high dose: later studies showed
`that lower doses were as effective and far
`better tolerated. The urgent need for the first
`effective anti-HIV [human immunodefitnency
`virus] treatment made the absence of dose.
`response information at the time of approval
`reasonable (with the condition that more data
`were to be obtained after marketing]. but in
`less urgent cases this approach is
`discouraged.
`Interactions Between Dose-Response and
`Time
`The choice of the size of an lndivrdual
`dose is often intertwined with the frequency
`ofdoSing. In general. when the dose interval
`is long compared to the half-life of the drug.
`attention should be directed to the
`pharmacodynemic basis for the chosen
`dostrig interval. For example. there might be
`a comparison of the long dose interval
`regimen with the seine use in a more
`divided regimen. looking. where this is
`feasible. for
`rststenca of desired effect
`throughout
`e dose interval and for adverse
`effects associated with blood level peaks.
`Within a stngle dose interval. the dose-
`response relationships at peak and trough
`blood levels may differ and the relationship
`could depend on the dose interval chosen.
`Dose-response studies should take time
`into account in a variety of other ways. The
`study period at a given dose should be long
`enough for the full-effect to be realized.
`whether delay is the result of
`pharmacokirietic or phannaoodynamtc
`factors. The dose-response may also be
`different for morning versus evening dostng.
`Similarly. the dosesresporise relationship
`during early dosing may not be the same as
`in the subsequent maintenance dosing
`period. Responses could also be related to
`cumulative dose. rather than daily dose. to
`duration of exposure {e.g.. techyphylaxis.
`tolerance. or hysteresis] or to the
`relationships of closing to meals.
`[1. Obtaining DosevReaponse Information
`Dose-Response Assessment Should Be an
`Integral Port ofDrug Development
`Assessment of dose-response should be an
`integral component of drug development
`with studies designed to assess dose-
`reaponsa an inherent part ofestablisliing the
`safety and effectiveness of the drug. if
`development of dosa~response information is
`built into the development process it can
`usually be accomplished with no loss of time
`and minimal extra effort compared to
`development plans that ignore dose-
`responSe.
`
`Studies in life-Threatening Diseases
`In particular therapeutic areas. different
`therapeutic and investigational hehavmrs
`
`ATI 1014-0002
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`ATI 1014-0002
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`55974
`Federal Register it Vol. 59. No. 216 it Wednesday November 9. 1994 i' Notices
`
`
`have evolved: these affect the kinds of
`studies typically carried out. Parallel dose-
`response study designs with placebo. or
`placebo-controlled titration study deSigns
`[very effective designs. typically used in
`studies of angina. depression. hypertension.
`etc.) would not be
`table in the study of
`some conditions. such as life-threatening
`infections or potentially curable tumors. at
`least if there were effective treatments
`known. Moreover. because in those
`therapeutic areas considerable torticity could
`he accepted. relatively high doses of drugs
`are usually chosen to achieve the greatest
`possible beneFiCial effect rapidly. This
`approach may lead to recommended doses
`that deprive some patients ei'tbe potential
`benefit ofa drug by inducing toxicity that
`leads to cessation of therapy. 0n the other
`hand, use of low, possibly subeffective.
`doses, or of titration to dasu'ed effect may be
`unacceptable. as an initial failure in these
`cases may represent an opportunity for cure
`forever lost.
`Nonetheless. even for life-threatening
`diseases. drug developers should always be
`weighing the gains and disadvantages of
`varying regimens and considering how best
`to cheese dose. dose-interval and dose-
`esoalation steps. Even in indications
`involving life-threatening diseases. the
`highest tolerated dose. or the dose with the
`largest effect on a surrogate market will not
`always be the optimal dose. Where only a
`single dose is studied. blood concentration
`data. which will almost always show
`considerable indivrdua] variability due to
`phamiacoldnetic differences. may
`retrospectively give clues to possible
`concentration-response relationships.
`Use oflosl a single dose has been typical
`of large-scale intervention studies [e.g.. post-
`myocardial infarction studies] because of the
`large sample sizes needed. in planning an
`intervention study. the potential advantages
`of studying more than a single dose should
`be considered. in some cases. it may be
`possible to simplify the study by collecting
`less information on each patient. allowing
`study of a larger population treated with
`several doses without significant increase in
`costs.
`
`Regulatory Considerations When Dose-
`Response Date Are bnpedect
`Even welhlaid plans are not invariably
`successful. An otherwise wall»destgned dose-
`respoose study may have utilized doses that
`were too high. or too close together. so that
`all appear equivalent (albeit su nor to
`placebo]. In that case. there is
`e possibility
`that the lowest dose studied is still greater
`than needed to exert the drug's minimum
`effect. Nonetheless. an acceptable balance of
`observed undesired affects and beneficral
`effects might make marketing at one of the
`doses studied reasonable. This dectsion
`would be easiest. of course. if the drug had
`special value. but even if it did not. in light
`of the studies that partly defined the proper
`dose range. further dose-finding might be
`pursued in the postmarketing period.
`Similarly. although seeking dose response
`data should be a goal of every development
`program. ap
`val based on data fiom studies
`using stints... single dose or a defined dose
`
`range [but without valid dose response
`information) might be appropriate where
`benefit from a new therapy in treating or
`preventing a serious disease is clear.
`Examining the Entire Database for Dose-
`Besponse information
`In addition to seeking dose-response
`information from studies specifically
`destgned to provide it. the entire database
`should be exempted Intensrvely for possible
`dose-response effects. The limitations
`imposed by certain study design features
`should. of course. be appreciated. For
`example. many studies titrete the dose
`upward for safety reasons. As most side
`effects of drugs occur early and may
`disappear with continued treannani. this can
`result in a spunously higher rate of
`undesirable effects at the lower doses.
`Similarly. in studies where patients are
`titrated to a desired response. those patients
`relatively unresponsive to the drug are more
`likely to receive the higher dose. giving an
`apparent. but misleading. inverted "U-
`shaped" dosavresponee curve. Despite such
`limitations. cilrucal data from all sources
`should be analyzed for dose-related effects
`using multivariate or other approaches. even
`if the analyses om yield principally
`hypotheses. not definitive conclusions. For
`example. an inverse relation of effect to
`weight or creatiaine clearance could reflect a
`dose-related covariate relationship. If
`phairnacokinatlc screening (obtaininga small
`number of sleadymtale blood concentration
`measurements in most Phase 2 and Phase 3
`study patients] is carried out. or if other
`approaches to obtaining drug concentrations
`during trials are used. a relation of effects
`(desrrable or undesirable] to blood
`concentrations may be discerned. The
`relatiooslup may by itself be a persuasive
`description of concentration-response or may
`suggest further study.
`111. Study Designs for Assessing Dose
`Response
`General
`
`The choice of study design and study
`population in dose-response trials will
`depend on the phase of development. the
`therapeutic indication under investigation.
`and the severity of the disease in the patient
`population of interest. For example. the lack
`of appropriate salvage therapy for life-
`threatening or serious conditions with
`irreversible outcomes may ethically preclude
`conduct of studies at doses below the
`maxtmum tolerated dose. A homogeneous
`patient population will generally allow
`achievement of study objectives with small
`numbers of subjects given each treatment On
`the other hand. larger. more diverse
`populations allow detection of potentially
`important covariate effects.
`In general. useful dose-response
`information is best obtained from trials
`specifically designed to compare several
`doses. A comparison of results from two or
`more controlled trials with single fixed doses
`might sometimes be informative, e.g.. if
`control groups were similar. although even in
`that case. the many across-study differences
`that occur in separate trials usually make this
`approach unsatisfactory. It is also possible in
`
`some cases to derive. retrospectively. blood
`concentration-response relationships from
`the variable concentrations attained in a
`fixed-dose tnal. While these analyses are
`potentially confounded by disease severity or
`other patient factors. the information can be
`useful and can g'oide' subsequent studies.
`Cenducting dose-response studies at an early
`stage of clinical development may reduce the
`number of failed Phase 3 trials. speeding the
`dmg development process and conserving
`development resources.
`Pharmacolunetic infon'naticn can be used
`to choose doses that ensure adequate spread
`of attained concentration-response values
`and dhmnish or eliminate overlap between
`attained concentrations in dose-response
`trials. For drugs with high phem‘iacokinetic
`variability. a greater spread of doses could be
`chosen. Alternatively. the dosing groups
`could beiadivrduaiieed by adjusting for
`pharmacokinetic oovanates (e.g.. correction
`for weight. lean body mass. or renal function)
`or a concentration-controlled study could be
`carried out.
`As a practical matter. valid dose—response
`data can be obtained more readily when the
`response is measured by a continuous or
`categorical variable. is relatively rapidly
`obtained after therapy is started. and is
`rapidly dissipated after therapy is stopped
`(e.g.. blood pressure. analgesia.
`bronchodilation]. In this case. a Wider range
`of study designs can be used and relatively
`small. simple studies can give useful
`information. Placebo-controlled individual
`Suhyect titration designs typical of many early
`drug development studies. for example.
`properly conducted and analyzed
`(quantitative analysis that models and
`estimates the population and individual
`dose-response relationships}. can give
`guidance for more definitive parallel. fixed-
`dose. dose-response studies or may be
`definitive on their own.
`In contrast. when the study endpomt or
`adverse effect is delayed. persistent. or
`irreversible [e.g.. stroke or heart attack
`prevention. asthma prophylaxrs. arthritis
`treatments with late onset response, survival
`in cancer. treatment of depression}. titration
`and simultaneous assessment of response is
`usually not possible. and the parallel dose-
`responsa study is usually needed. The
`parallel dose-response study also offers
`protection against missing an effective dose
`because ol'an inverted "U-shaped" [umbrella
`or bell-shaped) dose-response curve. where
`higher doses are less effective than lower
`doses. a response that can occur. for example.
`with mixed agonist-sntagonists.
`Trials intended to evaluate dose- or
`concentration-response should be well-
`ooritrolled. using randomization and blinding
`(unless blinding is unnecessary or
`impossible] to assure comparability of
`treatment groups and to minunlze potential
`patient. investigator. and analyst bias. and
`should be of adequate size.
`it is important to choose as wide a range
`of doses as is compatible with practicality
`and patient safety to discern clinically
`meaningful differences. This is especially
`important where there are no pharmacologic
`or plausible surrogate endpciots to give
`initial guidance es to dose.
`
`ATI 1014-0003
`
`ATI 1014-0003
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`55975
`Federal Register l Vol. 59. No. 216 I Wednesday, November 9, 1994 1’ Notices
`
`Specific Trial Designs
`A number of specific study deSigns can he
`used to assess dose-response. The same
`approaches can also he used to measure
`concentration-response relationships.
`Although not intended to be an exhaustive
`list. the following approaches have been
`shown to be useful ways of deriirin valid
`dose-response infomation. Seine estgus
`outlined in this guidance are better
`established than others. but all are worthy of
`consideration. These desi
`s can be e plied
`to the study of establish
`clinical on points
`or surrogate endpornta.
`1. Parallel Dose-Response
`Randomization to several fixed-dose
`groups [the randomized parallel dose-
`response study) is simple in concept and is
`a deal
`that has had extensive use and
`coast arable success. The fixed dose is the
`final or maintenance dose; patients may be
`placed Immediately on that dose or titrated
`gradually (in a scheduled "forced" titration]
`to it if that seems safer. in either case. the
`final dose should be maintained for a time
`adequate to allow the dose-response
`comparison. Although including a placebo
`group in dose-response studies is dean-able.
`it is not theoretically necessary in all cases;
`a positive slo is. even without a placebo
`group. provi es evidence of a drug effect. To
`measure the absolute size of the drug effect.
`however. a placebo or comparator with very
`limited effect on the endpoint of interest is
`usually needed..Moreovar. because a
`difference between drug groups and placebo
`unequivocally shows effectiveness. inclusmn
`of a placebo group can salvage. in
`. a
`study that used doses that were el
`too high
`and. therefore. showed no dose-response
`slope. by showing that all doses were
`superior to placebo. in princtple. being able
`to detect a statistically significantdiffarenoa
`in pair-wise comparisons between doses is
`not necessary if a statistically significant
`trend [upward slope] across doses can be
`established using all the date. it should be
`demonstrated. however. that the lowest
`dosels] tested, if it is to be recommended. has
`a statistically significant and clinically
`mean
`1 effect.
`The parallel dose-response study gives
`group mean {population-average) dose-
`responsa. not the distribution or shape of
`individual dose-response curves.
`It is all too common to discover. at the end
`of a parallel dose-response study. that all
`doses were too high [on the plateau of the
`dose-response curve]. or that doses did not go
`high enough. A formally planned interim
`analysis (or other multi-stage design) might
`detect such a problem and allow study of the
`proper dose range.
`As with any placebo-controlled trial. it
`may also be useful to include one or more
`doses of an active drug control. inclusion of
`both placebo and active control groups
`allows assessment of "assay sensitivity,
`permitting a distinction between an
`ineffective drug and an ”ineffectiVe" (null.
`no test] study. Companson of dose-response
`curves for test and control drugs. not yet a
`common design. may also represent a more
`valid and informative comparative
`effectivenessisafety study than comparison of
`Single doses of the two agents.
`
`The factorial trial is a spaCiai case of the
`parallel dose-response study to be considered
`when combination therapy is being
`evaluated. it is particularly useful when both
`agents are intended to affect the same
`response variable (a diuretic and another
`anti-hypertensive. for ample}. or when one
`drug is intended to mitigate the side effects
`of the other. These studies can show
`effectiveness [a contribution of each
`component of the combination] and. in
`addition. provtde dosing information for the
`drugs used alone and together.
`A factorial trial employs a parallel fixed-
`dose design with a range of doses of each
`separate drug and some or all combinations
`of these doses. The sample size need not be
`large enough to distinguish single cells from
`each other in pair-wise comparisons because
`all of the data can he used to derive dose-
`reaponsa relationships for the single agents
`and combinations. re. a dose-response
`surface. These trials. therefore. can be of
`moderate size. The doses and combinations
`that could be approved for marketing might
`not be limited to the actual doses studied but
`might include doses and combinations in
`between those studied. There may be some
`exceptions to the ability to rely entirely on
`the response surface analysis in choosing
`doseis]. At the low and of the dose range. if
`the doses used are lower than the recognized
`effective doses of the single agents. it would
`ordinarily be important to have adequate
`evidence that these can be distinguished
`from placebo in a pair-wise comparison. One
`way to do this in the factorial study is to have
`the lowest dose combination and placebo
`groups be somewhat larger than other groups:
`another is to have a separate study of the
`low-dose combination. Also. at the high and
`of the dose range. it may be necessary to
`confirm the contribution of each component
`to the overall effect.
`
`2. Crossover DosevResporise
`A randomized multiple aces-over study of
`different doses can be successful if drug
`effect develops rapidly and patients return to
`baseline conditions quickly after cessation of
`therapy. if responses are not Irreversible
`(cure. death]. and if patientsheve reasonably
`stable disease. This design suffers. however.
`from the potential problems of all cross-over
`studies: it can have analytic problems if there
`are many treatment withdrawals: it can be
`quite long in duration for an indivtdual
`patient-and there is often uncertainty about
`carry-over effects {longer treatment periods
`may minimise this problem]. baseline
`comparability after the first period. and
`period-by-treatrnant interactions. The length
`of the trial can be reduced by approaches that
`do not require all patients to receive each
`dose. such as balanced incomplete block
`designs.
`The advantages of the design are that each
`individual receives several different doses so
`that the distribution of individual dose-
`reaponae curves may be estimated. as well as
`the population average curve. and that,
`compared to a parallel design. fewer patients
`may be needed. Also. In contrast to titration
`designs. dose and time are not confounded
`and carry-over effects are better assessed.
`
`3. Forced Titration
`
`A forced titration study. where all patients
`move through a series of naing doses. is
`similar in concept and limitations to a
`randomized multiple cross-over dose-
`responsa study. sites i that assignment to
`dose levels is ordere . not random. If most
`patients complete all doses. and if the study
`is controlled with a parallel placebo group.
`the forced titration study allows a series of
`comparisons of an entire randomized group
`given several doses of drug with a concurrent
`placebo. lust as the parallel fixed-dose trial
`does. A critical disadvantage is that. by itself.
`this study design cannot distinguish response
`to increased dose from response to increased
`time on drug therapy or a cumulative drug
`