`
` 55972 Federal Register / Vol. 59, No. 216 / Wednesday November 9, 1994 / Notices
`
`Food and Drug Administration
`[Docket No. 93D-0194]
`
`International Conference on
`Harmonisation; Dose-Response
`Information to Support Drug
`Registration; Guideline; Availability
`
`sponsors. The guideline describesthe
`been undertaken by regulatory
`DEPARTMENT OF HEALTH AND
`
`
`
`HUMAN SERVICES_—_—-authorities and industry associations to value and uses of dose-response
`information andthe kinds of studies
`promoteinternational harmonization of
`that can obtain such information, and
`regulatory requirements. FDA has
`participated in many meetings designed
`fives specific guidance to manufacturers
`to enhance harmonization andis
`on the kinds of information they should
`obtain.
`committed to seeking scientifically
`In the past, guidelines have generally
`based harmonized technical procedures
`been issued under§ 10.90(b) (21 CFR
`for pharmaceutical development. One of
`the goals of harmonization 1sto identify
`10.90(b)), which provides for the use of
`and then reducedifferences 1n technical
`guidelines to state procedures or
`requirements for drug development.
`standardsofgeneralapplicability that
`(CH was organized to provide an
`are notlegal requirements butthat are
`opportunity for harmonization
`acceptable to FDA. The agency 1s now
`initiatives to be developed with input
`in the processof revising § 10.90(b).
`from both regulatory and industry
`Therefore, the guideline is not being
`representatives. FDA also seeks input
`issued underthe authority of current
`from consumerrepresentatives and
`§ 10.90(b), and it does not create or
`others. ICH 1s concerned with
`confer any nghts, privileges, or benefits
`harmonization of technical
`for or on any person, nor doesit operate
`requirements for the registration of
`to bind FDA 1n any way.
`pharmaceutical products among three
`As with all of FDA's guidelines,the
`regions: The European Union, Japan,
`public 1s encouraged to submit written
`and the United States. The six ICH
`comments with new data or other new
`sponsors are the European Commission,
`information pertinent to this guideline.
`The comments 1n the docketwill be
`the European Federation of
`Pharmaceutical Industry Associations,
`penodically reviewed, and where
`the Japanese Ministry of Health and
`appropnate, the guideline will be
`Welfare, the Japanese Pharmaceutical
`amended.The public will be notified’of
`Manufacturers Association, FDA, and
`any such amendments througha notice
`the U.S. Pharmaceutical Research and
`in the Federal Register.
`Manufacturers of America. The ICH
`Interested persons may at any time,
`Secretariat, which coordinates the
`submit written comments on the
`preparation of documentation, 1s
`guideline to the Dockets Management
`providedby the International
`Branch (address above). Two copies of
`Federation of Pharmaceutical
`any comments are to be submitted,
`Manufacturers Associations (IFPMA).
`exceptthe individuals may submit one
`The ICH Steering Committee includes
`copy. Commentsare to be 1dentified
`representatives from each of the ICH
`with the docket number found in
`sponsors and IFPMA, as well as
`brackets in the headingof this
`observers from the World Health
`document. The guideline and received
`Orgamization, the Canadian Health
`comments may be seen 1n the office
`Protection Branch, and the European
`above between 9 a.m. and 4 p.m.,
`Free Trade Area.
`Mondaythrough
`Fnday.
`At a meeting held on March 8, 9, and
`Thetextof the final guidelinefollows:
`10, 1993, the ICH Steering Committee
`Dose-Response Information to Support Drug
`agreedthat the draft tripartite guideline
`Registration
`entitled “Dose-Response Information To
`I. Introduction
`Support Drug Registration” should be
`madeavailable for comment. (The
`document1s the productof the Efficacy
`Export Working Group of ICH.)
`Subsequently the draft guideline was
`madeavailable for commentby the
`European UnionandJapan, as well as
`by FDA(see 58 FR 37402, July 9, 1993),
`in accordancewith their consultation
`procedures. The comments were
`analyzed and the guideline wasrevised
`as necessary. At a meeting held on
`March 10, 1994, the ICH Steering
`Committee agreed that this final
`guideline should be published.
`With this notice,
`FDA 1s publishing a
`final guideline entitled ‘Dose-Response
`Information To Support Drug
`Registration.” It 1s applicable to both
`drugs and biological products. This
`guideline has been endorsedbyall ICH
`
`AGENCY: Food and Drug Admunistration,
`HHS.
`ACTION:Notice.
`
`SUMMARY’ TheFood and Drug
`Admunistration (FDA) is publishing a
`final guideline entitled “Dose-Response
`Information To Support Drug
`Registration.” The guideline1s
`applicable to both drugs and biological
`products This guideline was_prepared
`y the Efficacy Expert Working Group of
`the International Conference on
`Harmonisation of Technical
`Requirements for Registration of
`Pharmaceuticals for Human Use(ICH).
`The guideline describes why dose-
`response information 1s useful and how
`it should be obtained in the course of
`drug development. This information can
`help identify an appropmate starting
`dose as well as howto adjust dosage to
`the needsof a particular patient. It can
`also identify the maximum dosage
`beyond whichany added benefits to the
`patient would be unlikely or would
`produce unacceptable side effects. This
`guideline is intendedto help ensure that
`dose response information to support
`drugregistration 1s generated according
`to soundscientific principles.
`EFFECTIVE DATE: November9, 1994.
`ADDRESSES: Submit written comments
`on the guideline to the Dockets
`Management Branch (HFA~305), Food
`and Drug Administration, 12420
`Parklawn Dr., rm. 1-23, Rockville, MD
`20857 Copies of the guideline are
`available from the CDER Executive
`Secretanat Staff (HFD-8), Centerfor
`Drug Evaluation and Research, Food
`and Drug Administration, 7500 Standish
`Pl., Rockville, MD 20855.
`FOR FURTHER INFORMATION CONTACT:
`Regarding the guideline: Robert
`Temple, Center for Drug Evaluation
`and Research (HFD~—100), Food and
`Drug Administration, 5600 Fishers
`Lane, Rockville, MD 20857 301—
`443-4330.
`Regarding ICH: Janet Showalter,
`Office of Health Affairs (HFY-1),
`Food and Drug Administration,
`5600 Fishers Lane, Rockville, MD
`20857 301-443-1382.
`SUPPLEMENTARYINFORMATION: In recent
`years, many importantinitiatives have
`
`Purpose of Dose-Response Information
`Knowledgeof the relationships among
`dose, drug concentration in blood, and
`clinical response (effectiveness and
`undesirable effects) 1s 1mportant for the safe
`and effective use of drugs in individual
`patients. This informationcan help identify
`an appropriate starting dose, the best way to
`adjust dosage to the needsofa particular
`patient, and a dose beyond whichincreases
`would be unlikely to provide added benefit
`or would produce unacceptableside effects.
`Dose-concentration, concentration- and/or
`dose-response information 1s used to prepare
`dosage and administration instructions in
`productlabeling. In addition, knowledge of
`dose-response may provide an economical
`approach to global drug development, by
`enabling multiple regulatory agencies to
`make approval decisions from a common
`database.
`
`ATI 1014-0001
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`ATI v. ICOS
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`IPR2018-01183
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`ATI 1014-0001
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`ATI v. ICOS
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`55973
`Federal Register / Vol. 59, No. 216 / Wednesday November 9, 1994 / Notices
`
`Historically, drugs have often beeninitially
`marketed at what were later recognized 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., hypokalerma and other
`metabolic disturbances with thiazide-type
`diuretics in hypertension). This situation has
`been improved by attemptsto find the
`smallest dose with a discernible usefuleffect
`or a maximum dose beyond whichnofurther
`beneficial effect 1s seen, but practical study
`designs donotexistto allow for precise
`determination of these doses. Further,
`expanding knowledgeindicates that the
`concepts of minimum effective dose and
`maximum useful dose do not adequately
`account for individual differences and do not
`allow a comparison, at various doses, of both
`beneficial and undesirableeffects. Any given
`dose provides a mixture ofdesirable and
`undesirable effects, with no single dose
`necessarily optimal for all patients.
`Use of Dose-Response Information in
`Choosing Doses
`What1s mosthelpful in choosing the
`starting dose of a drug 1s knowing the shape
`and location of the population (group)
`average dose-response curve for both
`desirable and undesirable effects. Selection
`of dose 1s best based on that information,
`together with a judgment abouttherelative
`importanceofdesirable and undesirable
`effects. For example,a relatively high starting
`dose (on ornear theplateauof the
`effectiveness dose-response curve) might be
`recommendedfor a drug with a large
`demonstrated separation between its useful
`and undesirable dose ranges or where a
`rapidly evolving disease process demands
`rapid effective intervention. A high starting
`dose, however, might be a poor choice for a
`drug with a small demonstrated separation
`betweenits useful and undesirable dose
`ranges. In these cases, the recommended
`starting dose mightbest be a low dose
`exhibiting a clinically umportanteffect in
`evena fraction of the patient population,
`with the intentto titrate the dose upwardsas
`long as the drugis well tolerated. Choice of
`a starting dose mightalso be affected by
`potential intersubyect variability in
`pharmacodynamicresponse to a given blood
`concentrationlevel, or by anticipated
`intersubject pharmacokinetic differences,
`such ascould arise from nonlinear kinetics,
`metabolic polymorphism,or a high potential
`for pharmacokinetic drug-druginteractions.
`In thesecases, a lowerstarting 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 choicesas to the
`appropriatestarting doses, dose-titration
`steps, and maximum recommended dose,
`based on different perceptions of msk/benefit
`relationships. Valid dose response data allow
`the use of such judgment.
`In adjusting the dose 1n an individual
`patientafter observing the responseto an
`initial dose, what would be most helpfulis
`knowledge of the shape of individual dose-
`response curves, which1s usually not the
`same as the population (group) average dose-
`
`response curve. Study designs that allow
`estimationofindividual dose-response
`curves could therefore be useful in guiding
`titration, although experience with such
`designs and theiranalysis 1s very limited.
`In utilizing dose-response information, it 1s
`importantto identify, to the extent possible,
`factors that lead to differences in
`pharmacokinetics of drugs among
`individuals, including demographicfactors
`(e.g., age, gender,race), other diseases(e.g.,
`renalor hepatic failure), diet, concurrent
`therapies, or individual charactenistics(e.g.,
`weight, body habitus, other drugs, metabolic
`differences).
`
`Uses of Concentration-Response Data
`Where a drug can be safely andeffectively
`given only with blood concentration
`monitoring, the value of concentration-
`response information 1s obvious. In other
`cases, an established concentration-response
`relationship 1s often not needed, but may be
`useful: (1) For ascertaining the magnitude of
`the clinical consequences of pharmacokinetic
`differences, such as those dueto drug-disease
`(e.g, renal failure) or drug-drug interactions;
`or(2) for assessing the effectsof the altered
`pharmacokinetics of new dosage forms(e.g.,
`controlled release formulation) or new
`dosage regimens withoutneed for additional
`clinical trial data, where such assessmentis
`permitted by regional regulations.
`Prospective randomized concentration-
`responsestudiesare obviously critical to
`defining concentration monitoring
`therapeutic ‘‘windows, but are also useful
`when pharmacokinetic variability among
`patients 1s great; in that case, a concentration-
`response relationship may in principle be
`discerned 1n a prospective study with a
`smaller numberof subjects than could the
`dose-response relationship in a standard
`dose-responsestudy. Notethat collection of
`concentration-response information does not
`imply that therapeutic blood level
`monitoring will be needed to administer the
`drug properly. Concentration-response
`relationships can be translated into dose-
`response information. Concentration-
`response 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
`undesirable or desirable pharmacologic
`effect) are defined, the drug canbe titrated
`accordingto patient response without the
`need for further blood level monitoring.
`Problems With Titration Designs
`A study design widely used to demonstrate
`effectivenessutilizes dosetitration to some
`effectiveness or safety endpoint. Such
`titration designs, without careful analysis, are
`usually not informative about dose-response
`relationships. In manystudies, there 1s a
`tendency to spontaneous improvementover
`timethat 1s noteasily distinguishable from
`an increased response to higher doses or
`cumulative drug exposure. This leads to a
`tendency to choose, as a recommendeddose,
`the highest dose used in such studies that
`wasreasonably well tolerated. Historically,
`this approachhasoften led to a dose that was
`
`well in excess of what wasreally necessary,
`resulting in mcreased undesirableeffects,
`e.g., to high-dose diuretics used for
`hypertension. In somecases, notably where
`an early answeris essential, the titration-to-
`highest-tolerable-dose approach1s
`acceptable, because it often requires a
`minimum number ofpatients. For example,
`the first marketing of zidovudine (AZT)for
`treatmentof people with acquired rmmune
`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 thefirst
`effective anti-HIV (human immunodeficiency
`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 1s
`discouraged.
`Interactions Between Dose-Response and
`Time
`The choiceof the size of an individual
`dose is often intertwined with the frequency
`of dosing. In general, when the dose interval
`1s long comparedto thehalf-life of the drug,
`attention should be directed to the
`pharmacodynamic basisfor the chosen
`dosing interval. For example, there might be
`a comparison ofthe wee dose interval
`regimen with the same dose in a more
`divided regimen,looking, where this 1s
`feasible, for
`persistence of desired effect
`throughout the dose intervaland for adverse
`effects associated with blood level peaks.
`Within a single dose interval, the dose-
`response relationshipsat peak and trough
`blood levels may differ and the relationship
`could dependonthe dose interval chosen.
`Dose-response studies should take time
`into account1n a variety of other ways. The
`study periodat a given dose should be long
`enough for the full-effect to be realized,
`whetherdelay1s the result of
`pharmacokinetic or pharmacodynamic
`factors. The dose-response mayalso be
`different for morning versus evening dosing.
`Similarly, the dose-response relationship
`during early dosing may notbe the same as
`in the subsequent maintenance dosing
`period. Responsescouldalso be related to
`cumulative dose, rather than daily dose, to
`duration of exposure (e.g., tachyphylaxis,
`tolerance, or hysteresis) or to the
`relationships of dosing to meals.
`II. Obtaining Dose-Response Information
`Dose-Response Assessment Should Be an
`Integral Part of Drug Development
`Assessmentof dose-response should be an
`integral componentof drug development
`with studies designed to assess dose-
`response an inherentpart of establishing the
`safety and effectiveness of the drug.If
`development of dose-response information 1s
`built into the developmentprocess it can
`usually be accomplished with noloss of time
`and minimal extra effort compared to
`development plans that ignore dose-
`response.
`
`Studies in Life-Threatening Diseases
`In particular therapeuticareas, different
`therapeutic andinvestigational behaviors
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`55974
`Federal Register / Vol. 59, No. 216 / Wednesday November 9, 1994 / Notices
`
`
`have evolved; these affect the kinds of
`studies typically carned out. Parallel dose-
`response study designs with placebo, or
`placebo-controlledtitration study designs
`(very effective designs, typically used in
`studies of angina, depression, hypertension,
`etc.) would not be acceptable in the study of
`some conditions, such aslife-threatening
`infections or potentially curable tumors, at
`least if there were effective treatments
`known. Moreover, because in those
`therapeutic areas considerable toxicity could
`be accepted, relatively high doses of drugs
`are usually chosen to achievethe greatest
`possible beneficial effect rapidly. This
`approach maylead to recommendeddoses
`that deprive somepatients of the potential
`benefit of a drug by inducing toxicity that
`leads to cessation of therapy. On the other
`hand, use oflow, possibly subeffective,
`doses,or oftitration to desired effect may be
`unacceptable, as an initial failure in these
`cases may represent an opportunity for cure
`foreverlost.
`Nonetheless, even forlife-threatening
`diseases, drug developers should always be
`weighing the gains and disadvantages of
`varying regimens and considering how best
`to choose dose, dose-interval and dose-
`escalation steps. Even in indications
`involving life-threatening diseases, the
`highesttolerated dose, or the dose with the
`largest effect on a surrogate marker will not
`always be the optimal dose. Where only a
`single dose 1s studied, blood concentration
`data, which will almost always show
`considerable individual variability due to
`pharmacokinetic differences, may
`retrospectively give clues to possible
`concentration-responserelationships.
`Useofjust a single dose has been typical
`of large-scale intervention studies(e.g., post-
`myocardialinfarction studies) becauseof 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
`sgveral doses without significant increase in
`costs.
`
`Regulatory Considerations When Dose-
`Response Data Are Imperfect
`Even well-laid plansare not invariably
`successful. An otherwise well-designed dose-
`response study may have utilized doses that
`were too high, or too close together, so that
`all appear equivalent (albeit superior to
`placebo). In that case, there 1s
`the possibility
`that the lowest dose studied1sstill greater
`than needed to exert the drug's maximum
`effect. Nonetheless, an acceptable balance of
`observed undesired effects and beneficial
`effects might make marketing at one ofthe
`doses studied reasonable. This decision
`would be easiest, of course,if the drug had
`special value, but evenifit 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, approval based on data from studies
`using afixed single dose or a defined dose
`
`range (but without valid dose response
`information) might be appropriate where
`benefit from a new therapyin treating or
`preventing a serious disease 1s clear.
`Examining the Entire Database for Dose-
`Response Information
`In addition to seeking dose-response
`information from studies specifically
`designed to provideit, the entire database
`should be examined intensively for possible
`dose-responseeffects. The limitations
`imposed by certam study design features
`should, of course, be appreciated. For
`example, manystudiestitrate the dose
`upwardfor safety reasons. As most side
`effects of drugs occur early and may
`disappear with continued treatment, this can
`result 1n a spuriously higherrate of
`undesirable effects at the lower doses.
`Similarly, in studies where patients are
`titrated to a desired response, those patients
`relatively unresponsiveto the drug are more
`likely to receive the higher dose, giving an
`apparent, but misleading, inverted “U-
`shaped" dose-response curve. Despite such
`limitations, clinical data from all sources
`should be analyzed for dose-related effects
`using multivariate or other approaches, even
`if the analyses can yield principally
`hypotheses, not definitive conclusions. For
`example, an inverse relation of effect to
`weightor creatinine clearance could reflect a
`dose-related covariate relationship.If
`pharmacokinetic screening (obtaininga small
`numberof steady-state blood concentration
`measurements in most Phase 2 and Phase 3
`study patients) 1s carried out, orif other
`approaches to obtaining drug concentrations
`during trials are used,a relation ofeffects
`(desirable or undesirable) to blood
`concentrations may be discerned. The
`relationship may byitself be a persuasive
`description of concentration-response or may
`suggestfurther study.
`Ill. Study Designs for Assessing Dose
`Response
`General
`
`The choice of study design and study
`population in dose-responsetnalswill
`dependonthe phase of development, the
`therapeutic indication underinvestigation,
`andthe severity of the disease 1n the patient
`population of interest. For example, the lack
`of appropriate salvage therapy for life-
`threatening or serious conditions with
`ureversible outcomes may ethically preclude
`conduct ofstudies at doses below the
`maximum tolerated dose. A homogeneous
`patient population will generally allow
`achievementof study objectives with small
`numbers of subjects given each treatment. On
`the other hand, larger, more diverse
`populations allow detection ofpotentially
`unportant covariate effects.
`In general, useful dose-response
`informationis best obtained from trials
`specifically designed to compare several
`doses. A comparison ofresults 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-studydifferences
`that occur in separate trials usually make this
`approach unsatisfectory. It 1s also possible in
`
`some Cases to derive, retrospectively, blood
`concentration-response relationships from
`the variable concentrations attained in a
`fixed-dose trial. While these analyses are
`potentially confounded by disease severity or
`otherpatientfactors, the information can be
`useful and can guidesubsequentstudies.
`Conducting dose-response studies at an early
`stage of clinical development may reduce the
`number offailed Phase 3 trials, speeding the
`drug development process and conserving
`developmentresources.
`Pharmacokinetic information can be used
`to choose doses that ensure adequate spread
`of attained concentration-response values
`and diminish or eliminate overlap between
`attained concentrations in dose-response
`tnals. For drugs with high pharmacokinetic
`vartability, a greater spread of doses could be
`chosen. Alternatively, the dosing groups
`could beindividualized by adjusting for
`pharmacokinetic covariates (e.g., correction
`for weight, lean body mass,or rena] function)
`or a concentration-controlled study could be
`carried out.
`Asa practical matter, valid dose-response
`data can be obtained more readily when the
`response is measured by a continuousor
`categorical variable, 1s relatively rapidly
`obtainedafter therapy1s started, and 1s
`rapidly dissipated after therapy 1s stopped
`(e.g., blood pressure, analgesia,
`bronchodilation). In this case, a wider range
`of study designs can be used andrelatively
`small, simple studies can give useful
`information. Placebo-controlled individual
`subjecttitration 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 endpointor
`adverse effect 1s delayed, persistent, or
`irreversible (e.g., stroke or heart attack
`prevention, asthma prophylaxis, arthritis
`treatments with late onset response, survival
`in cancer, treatmentof depression),titration
`and simultaneous assessmentof response 13
`usually not possible, and the parallel dose-
`response study 1s usually needed. The
`parallel dose-response studyalso offers
`protection against missingan effective dose
`because ofan 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-antagonists.
`Trials intended to evaluate dose- or
`concentration-response should be well-
`controlled, using randomization and blinding
`(unless blinding is unnecessary or
`impossible) to assure comparability of
`treatment groups and to minumize potential
`patient, investigator, and analyst bias, and
`should be of adequatesize.
`It is important to choose as wide a range
`of doses as is compatible with practicality
`and patient safety to discern climecally
`meaningful differences. This is especially
`important where there are no pharmacologic
`or plausible surrogate endpoints to give
`mitial guidanceas te dase.
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`Specific Trial Designs
`A numberofspecific study designs can be
`used to assess dose-response. The same
`approaches can also be used to measure
`concentration-response relationships.
`Although not intended to be an exhaustive
`list, the following approaches have been
`shownto be useful ways of deriving valid
`dose-response information. Somedesigns
`outlined in this guidance are better
`established than others, but all are worthy of
`consideration. These designs can be applied
`to the study of established
`clinical endpoints
`or surrogate endpoints.
`1. Parallel Dose-Response
`Randomizationto several fixed-dose
`groups(the randomized parallel dose-
`response study) 1s simple in concept and is
`a design
`that has had extensive use and
`considerable success. Thefixed dose 1s 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
`adequateto allow the dose-response
`comparison. Although including a placebo
`group in dose-response studies 1s desirable,
`it 1s not theoretically necessary in all cases;
`a positive slope, even without a placebo
`group, provides evidence ofa drugeffect. To
`measure the absolute size of the drug effect,
`however, a placebo or comparator with very
`limited effect on the endpointofinterest 13
`usually needed. Moreover, because a
`difference between drug groups and placebo
`unequivocally shows effectiveness, inclusion
`of a placebo group can salvage, in
`8
`study that used doses thatwere all
`too high
`and, therefore, showed no dose-response
`slope, by showingthatall doses were
`superior to placebo. In principle, being able
`to detect a statistically significantdifference
`in pair-wise compansons between doses13
`not necessary if a statistically significant
`trend (upwardslope) across doses can be
`established using all the data.It should be
`demonstrated, however,that the lowest
`dose(s)tested,if it 1s to be recommended, has
`a statistically significant andclinically
`meaningful effect.
`The parallel dose-response study gives
`group mean (population-average) dose-
`response,notthe distribution or shape of
`individual dose-response curves.
`It is all too commonto discover, at the end
`of a parallel dose-responsestudy,thatall
`doses were too high (on the plateau of the
`dose-response curve), or that doses did not go
`high enough. A formally planned intenm
`analysis (or other multi-stage design) might
`detect such a problem andallow studyof the
`proper dose range.
`As with any placebo-controlledtrial, it
`mayalso be useful to include one or more
`doses of an active drug control. Inclusion of
`both placebo and active control groups
`allows assessmentof “assay sensitivity,
`permitting a distinction between an
`ineffective drug and an “ineffective” (null,
`no test) study. Comparison of dose-response
`curves for test and control drugs, not yet a
`common design, may also represent a more
`valid and informative comparative
`effectiveness/safety study than comparison of
`single doses of the two agents.
`
`Thefactorialtrial 1s a special case of the
`parallel dose-response study to be considered
`when combination therapy1s being
`evaluated.It 1s particularly useful when both
`agents are intended to affect the same
`response variable (a diuretic and another
`anti-hypertensive, for example), or when one
`drug 1s intendedto mitigate the side effects
`ofthe other. These studies can show
`effectiveness (a contribution of each
`componentof the combination) and, in
`addition, provide dosing informationfor the
`drugs used alone andtogether.
`A factorial tal 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 enoughto distinguish singlecells from
`each other in pair-wise comparisons because
`all of the data can be used to derive dose-
`response relationships for the single agents
`and combinations, 1.¢., a dose-response
`surface. These tnals, therefore, can be of
`moderatesize. 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 mmy be some
`exceptions to the ability to rely entirely on
`the response surface analysis in choosing
`dose(s). At the low endofthe dose range,if
`the doses used are lower than the recognized
`effective doses of the single agents, it would
`ordinarily be importantto have adequate
`evidence that these can be distinguished
`from placebo in a pair-wise comparison. One
`wayto do this in the factorial study 1s to have
`the lowest dose combination and placebo
`groups be somewhatlarger than other groups;
`anotheris to have a separate studyof the
`low-dose combination. Also,at the high end
`of the dose range,it may be necessary to
`confirm the contribution of each component
`to the overall effect.
`
`2. Cross-over Dose-Response
`A randomized multiple cross-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 notirreversible
`(cure, death), and if patients.have reasonably
`stable disease. This design suffers, however,
`from the potential problemsofall cross-over
`studies:It can have analytic problemsif there
`are many treatment withdrawals;it can be
`quite long in duration for an individual
`patient;-and there is often uncertainty about
`carry-over effects (longer treatment periods
`may minimize this problem), baseline
`comparability after the first period, and
`period-by-treatmentinteractions. The length
`ofthe tral can be reduced by approaches that
`do not require all patients to receive each
`dose, such as balanced incomplete block
`designs.
`The advantages ofthe design are that each
`individualreceives several different doses so
`that the distributionof individual dose-
`response curves may be estimated, as well as
`the population average curve, andthat,
`comparedto a parallel design, fewer patients
`may be needed. Also,in contrastto titration
`designs, dose and timeare not confounded
`and carry-overeffects are better assessed.
`
`3. Forced Titration
`
`A forced titration study, where all patients
`movethrough a seriesof rising doses, is
`sumilar in concept andlimitations to a
`randomized multiple cross-over dose-
`response study, ioe that assignmentto
`dose levels is ordered, not random.If most
`patients complete all doses, and if the study
`1s controlled with a parallel placebo group,
`the forced titration study allows a senes of
`comparisonsof an entire randomized group
`given several doses of drug with a concurrent
`placebo, just as the parallel fixed-dose trial
`does. A critical disadvantage1s that,by itself,
`this study design cannotdistinguish response
`to increased dose from response to increased
`time on drug therapy or a cumulative drug
`dosageeffect. It is therefore an unsatisfactory
`design when response ig,delayed, unless
`treatmentat each dose is prolonged. Even
`where thetime until developmentofeffect 1s
`known to be short (from other data)