55972
`Federal Register / Vol. 59, No. 216 / Wednesday November 9, 1994 / Notices
`
`DEPARTMENTOF HEALTH AND
`HUMAN SERVICES
`
`Food and Drug Administration
`[Docket No. 930-0194]
`
`International Conference on
`Harmonisation; Dose-Response
`Information to Support Drug
`Registration; Guideline; Availability
`
`AGENCY:Food and Drug Administration,
`HHS.
`ACTION: Notice.
`
`SUMMARY* The Food and Drug
`Admunistration (FDA)1s publishing a
`final guideline entitled ‘Dose-Response
`Information To Support Drug
`Registration.” The guideline 1s
`applicable to both drugs and biological
`products. This guideline wasprepared
`by the Efficacy Expert Working Group of
`the Internationa] Conference on
`Harmonisation of Technical
`Requirementsfor Registration of
`Pharmaceuticals for Human Use (ICH).
`The guideline describes why dose-
`response information 1s useful and how
`it should be obtained 1n the course of
`drug development. This information can
`help identify an appropriate starting
`dose as well as how to adjust dosage to
`the needsofa particularpatient. It can
`also identify the maximum dosage
`beyond which any addedbenefits to the
`patient would be unlikely or would
`produce unacceptable side effects. This
`guideline 1s intended to help ensure that
`dose response information to support
`drug registration 1s generated according
`to soundscientific principles.
`EFFECTIVE DATE: November9, 1994.
`ADDRESSES: Submit written comments
`on the guidelineto the Dockets
`Management Branch (HFA-305), Food
`and Drug Administration, 12420
`Parklawn Dr., rm. 1-23, Rockville, MD
`20857 Copies ofthe guideline are
`available from the CDER Executive
`Secretariat Staff (HFD—8), Center for
`Drug Evaluation and Research, Food
`and Drug Adminstration, 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.
`SUPPLEMENTARY INFORMATION: In recent
`years, many importantinitiatives have
`
`been undertaken by regulatory
`authorities and industry associations to
`promoteinternational harmonization of
`regulatory requirements. FDA has
`participated in many meetings designed
`to enhance harmonization and1s
`committed to seekingscientifically
`based harmonized technical procedures
`for pharmaceutical development. One of
`the goals of harmonization1s to identify
`and then reducedifferences in technical
`requirements for drug development.
`CH wasorganized to provide an
`opportunity for harmonization
`initiatives to be developed with input
`from both regulatory and industry
`representatives. FDA also seeks input
`from consumerrepresentatives and
`others. ICH 1s concerned with
`harmonization of technical
`requirements for the registration of
`pharmaceutical products among three
`regions: The European Union,Japan,
`and the United States. The six ICH
`sponsors are the European Commission,
`the European Federation of
`Pharmaceutical Industry Associations,
`the Japanese Ministry of Health and
`Welfara, the Japanese Pharmaceutical
`Manufacturers Association, FDA, and
`the U.S. Pharmaceutical Research and
`Manufacturers of Amenca. The ICH
`Secretariat, which coordinates the
`preparation of documentation, 1s
`provided by the International
`Federation of Pharmaceutical
`Manufacturers Associations (IFPMA).
`The ICH Steering Committee includes
`representatives from each of the ICH
`sponsors and IFPMA, as well as
`observers from the World Health
`Orgamzation, the Canadian Health
`Protection Branch, and the European
`Free Trade Area.
`At a meeting held on March8, 9, and
`10, 1993, the ICH Steering Committee
`agreedthatthedraft tripartite guideline
`entitled “Dose-Response Information To
`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 comment by 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 was revised
`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 endorsed by all ICH
`
`sponsors. The guideline describes the
`value and uses of dose-response
`information and the kindsofstudies
`that can obtain such information, and
`gives specific guidance to manufacturers
`on the kindsof information they should
`obtain.
`In the past, guidelines have generally
`been issued under § 10.90(b) (21 CFR
`10.90(b)), which provides for the use of
`guidelines to state procedures or
`standards of general applicability that
`are not legal requirements but that are
`acceptable to FDA. The agency 1s now
`in the processof revising § 10.90(b).
`Therefore, the guideline 1s not being
`issued underthe authority of current
`§ 10.90(b), and it does not create or
`confer any nghts, privileges, or benefits
`for or on any person, nor does it operate
`to bind FDA 1n any way.
`As with all of FDA's guidelines, the
`public 1s encouraged to submit written
`comments with new data or other new
`information pertinent to this guideline.
`The comments1n the docket will be
`periodically reviewed, and where
`__
`appropriate, the guideline willbe
`amended. The public will be notified’ of
`any such amendments through a notice
`in the Federal Register.
`Interested persons may at any time,
`submit written comments on the
`guideline to the Dockets Management
`Branch (address above). Two copies of
`any commentsare to be submitted,
`except the individuals may submit one
`copy. Commentsareto be identified
`with the docket number found in
`brackets in the heading of this
`document, The guideline and received
`comments may be seen1n the office
`above between 9 a.m. and 4 p.m.,
`Mondaythrough Friday.
`Thetext of the final guideline follows:
`Dose-Response Information to Support Drug
`Registration
`I. Introduction
`
`Purpose of Dose-Response Information
`Knowledgeof the relationships among
`dose, drug concentration in blood, and
`clinical response(effectiveness and
`undesirable effects) 1s importantfor the safe
`and effective use of drugs in individual
`patients. This information can help identify
`an appropnatestarting dose, the best way to
`adjust dosageto the needs ofa particular
`patient, and a dose beyond which increases
`would be unlikely to provide added benefit
`or would produce unacceptable side 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
`approachto global drug development, by
`enabling multiple regulatory agencies to
`make approval decisions from a common
`database.
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`55973
`Federal Register / Vol. 59, No. 216 / Wednesday November 9, 1994 / Notices
`
`response curve. Study designs that allow
`estimation of individual dose-response
`curves could therefore be useful in guiding
`titration, although experience with such
`designs andtheir analysis ts 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 demographic factors
`(e.g., age, gender, race), other diseases(e.g.,
`renal or hepatic failure), diet, concurrent
`therapies, or individual characteristics (¢.g.,
`weight, body habitus, other drugs, metabolic
`differences).
`
`well in excess of what was really necessary,
`Historically, drugs have often been imitially
`marketed at what were later recognized as
`resulting in increased undesirable effects,
`excessive doses(i.e., doses well onto the
`2.g., to high-dose diuretics used for
`hypertension. In some cases, notably where
`plateau of the dose-response curve for the
`desired effect), sometimes with adverse
`an early answer1s essential, the titration-to-
`highest-tolerable-dose approach 1s
`consequences(e.g., hypokalemia and other
`acceptable, because it often requires a
`metabolic disturbances with thiazide-type
`minimum numberofpatients. For example,
`diuretics in hypertension). This situation has
`the first marketing of zidovudine (AZT)for
`been improvedby attemptsto find the
`smallest dose with a discernible usefuleffect
`treatment of people with acquired immune
`deficiency syndrome (AIDS) was based on
`or a maximum dose beyond which nofurther
`studies at a high dose;later studies showed
`beneficial effect 1s seen, but practical study
`that lower doses were aseffective and far
`designs do notexist to allow for precise
`determination of these doses. Further,
`better tolerated. The urgent need for thefirst
`effective anti-HIV (human immunodeficiency
`expanding knowledgeindicates that the
`virus) treatment madethe absenceof dose-
`concepts of minimum effective dose and
`Uses of Concentration-Response Data
`response informationat the time of approval
`maximum useful dose do not adequately
`accountfor mdividual differences and do not
`reasonable (with the condition that more data
`Where a drugcan besafely and effectively
`given only with blood concentration
`allow a comparison, at vanous doses, of both
`were to be obtained after marketing), but in
`less urgent cases this approach13s
`monitoring, the value of concentration-
`beneficial and undesirable effects. Any given
`discouraged.
`response information 1s obvious. In other
`dose provides a mixture of desirable and
`cases, an established concentration-response
`undesirable effects, with no single dose
`Interactions Between Dose-Response and
`relationship1s often not needed, but may be
`Time
`necessarily optima! forall patients.
`useful: (1) For ascertaining the magnitude of
`The choiceofthe s1ze of an individual
`Use ofDose-Response Information in
`the clinical consequences of pharmacokinetic
`Choosing Doses
`dose is often intertwined with the frequency
`differences, such as those dueto drug-disease
`of dosing. In general, when the dose interval
`What1s most helpful in choosing the
`(e.g, renal failure) or drug-drug interactions;
`1s long comparedto the half-life of the drug,
`starting dose of a drug 1s knowing the shape
`or (2) for assessing the effects of the altered
`attention should be directed to the
`and location of the population (group)
`pharmacokinetics of new dosage forms(e.g,
`pharmacodynamicbasis for the chosen
`controlled release formulation) or new
`average dose-response curvefor both
`desirable and undesirable effects. Selection
`dosing interval. For example, there might be
`dosage regimens without need for additional
`of dose is best based on that information,
`a comparisonof the long dose interval
`clinical trial data, where such assessment1s
`regimen with the same dose in a more
`together with a judgmentabouttherelative
`permitted by regional regulations.
`divided regimen, looking, where this is
`importanceof desirable and undesirable
`Prospective randomized concentration-
`feasible, for persistence of desired effect
`responsestudies are obviously critical to
`effects. For example,a relatively high starting
`throughoutthe dose interval and for adverse
`dose (on or near the plateau of the
`defining concentration monitoring
`effects associated with blood level peaks.
`effectiveness dose-response curve) might be
`therapeutic ‘windows, but are also useful
`Within a single dose interval, the dose-
`recommendedfor a drug with a large
`when pharmacokinetic variability among
`responserelationships at peak and trough
`demonstrated separation betweenits useful
`patients 1s great; in that case, a concentration-
`blood levels may differ and the relationship
`and undesirable dose ranges or where a
`response relationship may 1n pninciple be
`could dependon the dose interval chosen.
`rapidly evolving disease process demands
`discerned ina prospective study with a
`Dose-response studies should take time
`rapideffective intervention. A high starting
`smaller numberof subjects than could the
`into accountinavariety of other ways. The
`dose, however, might be a poor choice for a
`dose-responserelationship in a standard
`study period at a given dose should be long
`drug with a small demonstrated separation
`dose-response study. Note that collection of
`betweenits useful and undesirable dose
`enough forthe full-effect to be realized,
`concentration-response information does not
`whetherdelay1s the result of
`ranges.In these cases, the recommended
`imply that therapeutic blood level
`pharmacokinetic or pharmacodynamic
`starting dose might best be a low dose
`monitoring will be needed to administer the
`factors. The dose-response mayalso be
`exhibiting a clinically important effect in
`drug properly. Concentration-response
`different for morning versus evening dosing.
`even a fraction of the patient population,
`relationships can be translated into dose-
`Similarly, the dose-response relationship
`with the intentto titrate the dose upwards as
`response information. Concentration-
`during early dosing maynot be the same as
`long as the drug1s well tolerated. Choice of
`response information can also allow selection
`in the subsequent maintenance dosing
`a starting dose mightalso beaffected by
`of doses (based on the range of
`period. Responses could also berelated to
`potential intersubject variability in
`concentrations they will achieve) mostlikely
`cumulative dose, rather than daily dose, to
`pharmacodynamic responseto a given blood
`to lead to a satisfactory response.
`duration of exposure(e.g., tachyphylaxis,
`concentration level, or by anticipated
`Alternatively,if the relationships between
`tolerance, or hysteresis) or to the
`itersubject pharmacokinetic differences,
`concentration and observed effects (e.g., an
`relationships of dosing to meals.
`such as could arise from nonlinear kinetics,
`undesirable or desirable pharmacologic
`metabolic polymorphism,or a high potential
`effect) are defined, the drug can betitrated
`Il. Obtaining Dose-Response Information
`for pharmacokinetic drug-druginteractions.
`accordingto patient response without the
`Dose-Response Assessment Should Be an
`In these cases, a lower starting dose would
`needfor further blood level monitoring.
`Integral Part ofDrug Development
`protect patients who obtain higher blood
`Problems With Titration Designs
`concentrations.It 1s entirely possible that
`Assessmentof dose-response should be an
`different physicians and evendifferent
`A study design widely used to demonstrate
`integral componentof drug development
`effectivenessutilizes dose titration to some
`regulatory authorities, looking at the same
`with studies designed to assess dose-
`data, would makedifferent choices as to the
`effectiveness or safety endpoint. Such
`response an inherentpart of establishing the
`appropniate starting doses, dose-titration
`titration designs, without careful analysis, are
`safety and effectiveness of the drug. If
`steps, and maximum recommended dose,
`usually not informative about dose-response
`developmentof dose-response information is
`based on different perceptions of msk/benefit
`relationships. In manystudies, there 1s a
`built into the developmentprocess it can
`tendency to spontaneous improvement over
`relationships. Valid dose response data allow
`usually be accomplished with noloss of time
`the use of such judgment.
`time that1s not easily distinguishable from
`and minimal extra effort compared to
`In adjusting the dose in an individual
`al increased response to higher doses or
`developmentplans that :gnore dose-
`response.
`cumulative drug exposure. This leads to a
`patient after observing the response to an
`initial dose, what would be most helpful1s
`tendency to choose, as a recommended dose,
`the highest dose used in such studies.that
`knowledgeof the shape of individual dose-
`response curves, which1s usually not the
`was reasonably well tolerated. Historically,
`sameas the population (group) average dose-
`this approach hasoften led to a dose that was
`
`Studies in Life-Threatening Diseases
`In particular therapeutic areas, different
`therapeutic and investigational 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-controlled titration study designs
`(very effective designs, typically used in
`studies of angina, depression, hypertension,
`etc.) would not be acceptable 1n the study of
`someconditions, 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 achieve the greatest
`possible beneficial effect rapidly. This
`approach maylead to recommended doses
`that deprive somepatientsof the potential
`benefit of a drug by inducingtoxicity that
`leadsto cessation of therapy. On the other
`hand, useof low, 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 for life-threatening
`diseases, drug developers should always be
`weighing the gains and disadvantagesof
`varying regimens and considering how best
`to choose dose, dose-interval and dose-
`escalation steps. Even in indications
`involving life-threatening diseases, the
`highest tolerated dose, or the dose with the
`largest effect on a surrogate markerwill not
`always be the optimal dose. Where only a
`single dose1s studied, blood concentration
`data, which will almost always show
`considerable individual variability due to
`pharmacokinetic differences, may
`retrospectively give cluesto possible
`concentration-responserelationships.
`Useofjust a single dose has beentypical
`of large-scale intervention studies(e.g., post-
`myocardial infarction studies} because ofthe
`large sample sizes needed. In planning an
`intervention study, the potential advantages
`of studying more thana single dose should
`be considered. In somecases, it may be
`possible to simplify the study by collecting
`less information on each patient, allowing
`study of a larger population treated with
`saveral doses withoutsignificant increase in
`costs.
`
`Regulatory Considerations When Dose-
`Response Data Are Imperfect
`Even well-laid plans are not invariably
`successful. An otherwise well-designed dose-
`response study may haveutilized doses that
`were too high,or too close together, so that
`all appear equivalent (albeit supenorto
`placebo). In that case, there 1s the possibility
`that the lowest dose studied1s still 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 even if it did not, in light
`of the studiesthat partly defined the proper
`dose range,further dose-finding might be
`pursued in the postmarketing penod.
`Similarly, although seeking dose response
`data should be a goal of every development
`program, approval based on data from studies
`using a-fixed single dose or a defined dose
`
`range (but without valid dose response
`information) might be appropriate where
`benefit from a new therapy 1n treating or
`preventing a serious disease 1s clear.
`Examiningthe 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
`imposedby certain study design features
`should,of course, be apprectated. 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 in a spuriously higherrate of
`undesirable effects at the lower doses.
`Similarly, in studies where patients are
`titrated to a desired response, thosepatients
`relatively unresponsive to the drug are more
`likely to receive the higher dose, giving an
`apparent, but misleading, inverted “U-
`shaped” dose-response curve. Despite such
`limitations, climical 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 ofeffect to
`weight orcreatine clearance couldreflect a
`dose-related covariate relationship.If
`pharmacokinetic screening (obtaining a small
`numberofsteady-state blood concentration
`measurements in most Phase 2 and Phase 3
`study patients) 18 carned out, orif other
`approachesto obtaining drug concentrations
`duringtrials are used, a relation ofeffects
`(desirable or undesirable) to blood
`concentrations may be discerned. The
`relationship may by itself be a persuasive
`description of concentration-response or may
`suggest further study.
`Ill. Study Designs for Assessing Dose
`Response
`General
`
`The choice of study design and study
`population tn dose-responsetrials wil]
`depend on the phase of development, the
`therapeutic sndication under investigation,
`and theseverity of the disease mm the patient
`population of interest. For example, the lack
`of appropriate salvage therapy for life-
`threateningor serious conditions with
`irreversible outcomes mayethically preclude
`conductofstudies at doses below the
`maximum tolerated dose. A homogeneous
`patient population will generally allow
`achievementofstudy objectives with small
`numbers ofsubjects given each treatment. On
`the other hand, larger, more diverse
`populations allow detection of potentially
`important covanateeffects.
`In general, useful dose-response
`information is best obtained from trials
`specifically designed to compare several
`doses. A comparisonof results fram two or
`more controlled trials with single fixed doses
`might sometimes be informative, e.g., if
`contro! groups were similar, although even in
`that case, the many ecross-study differences:
`that occur in separate trials usually make this
`approach unsatisfectory.!t 1s also possible in
`
`some cases to denve,retrospectively, blood
`concentration-response relationships from
`the variable concentrations attained in 4
`fixed-dosetrial. While these analyses are
`potentially confounded by disease severity or
`otherpatient factors, the formation can be
`useful and can guide subsequentstudies.
`Conducting dose-responsestudies at an early
`stage of clinical development may reduce the
`numberof failed Phase 3 tnals, speeding the
`drug development process and conserving
`developmentresources.
`Pharmacokinetic information can be used
`to choose doses that ensure adequate spread
`of attamed concentration-response values
`and diminishoreliminate overlap between
`attained concentrations in dose-response
`trials. For drugs with high pharmacokinetic
`vartability, a greater spread of doses could be
`chosen. Alternatively, the dosing groups
`could be individualizedby adjusting for
`pharmacokinetic covariates (e.g., correction
`for weight, lean body mass, or rena] function)
`or a concentration-controlled study could be
`carried out.
`As a practical matter, valid dose-response
`data can be obtamed more readily when the
`response is measured by a continuous or
`categorical variable,1s relatively rapidly
`obtainedafter therapy 1s 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
`smal], simple studies can give useful
`information. Placebo-controlled individual
`subject titration designs typical of manyearly
`drug developmentstudies, for example,
`properly conducted and analyzed
`(quantitative analysis that models and
`estimates the population and individual.
`dose-response relationships), can give
`guidancefor more definitive parallel, fixed-
`dose, dose-response studies or may be
`definitive on their own.
`In contrast, when the study endpomt or
`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, treatment of depression), titration
`and simultaneous assessmentof response18
`usually not possible, and the parallel dose-
`responsestudy1s usually needed. The
`parallel dose-response study also offers
`protection against missing an effective dose
`because of an inverted “U-shaped” (umbrella
`or bell-shaped) dose-response curve, where
`higher doses are less effective than lower
`doses, & responsethat 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 minimize potential
`patient, investigator, and analyst bias, and
`should be of adequate size.
`It is umportant to choose as wide a range
`of doses as is compatible with practicality
`and patientsafety to discern clinically
`meaningfuldifferences. This is especially
`important where there are no pharmacologic
`or plausible surrogate endpointsto give
`initial guidance as to dose.
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`
`Specific Trial Designs
`A numberof specific study designs can be
`used to assess dose-response. The same
`approachescan 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 derivingvalid
`dose-response information. Some designs
`outlined in this guidance are better
`established than others, butall are worthy of
`consideration. These designs can be applied
`to the studyofestablished clinica] endpoints
`or surrogate endponnts.
`1, Parallel Dose-Response
`Randomization to several fixed-dose
`groups(the randomized parallel dose-
`response study)1s simple in concept and1s
`a design that has had extensive use and
`considerable success. The fixed 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 seemssafer. Jn 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 studies1s desirable,
`itis not theoretically necessary in all cases;
`a positive slope, even withouta placebo
`group, provides evidence of a drug effect. To
`measure the absolute s1ze of the drug effect,
`however, a placebo or comparator with very
`limited effect on the endpointofinterest18
`usually needed. Moreover, because a
`difference between drug groups and placebo
`unequivocally showseffectiveness, inclusion
`of a placebo group cansalvage, in part, a
`study that used dosesthat were all too high
`and, therefore, showed no dose-response
`slope, by showingthat all doses were
`superiorto placebo. In principle, being able
`to detecta statistically significantdifference
`in pair-wise comparisons between doses18
`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 and clinically
`meaningfuleffect.
`Theperalle)] dose-response study gives
`group mean (population-average) dose-
`response, notthe distribution or shape of
`individual dose-response curves.
`It is all too common to discover, at the end
`of a parallel dose-response study,thatall
`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) maght
`detect such a problem andallow studyofthe
`proper dose range.
`As with any placebo-controlledtral,it
`mayalso be useful to include one or more
`doses ofan 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,
`notest) study. Comparison of dose-response
`curves for test and control drugs, not yet a
`commondesign, may also represent a more
`valid and informative comparative
`effectiveness/safety study than comparison of
`single doses of the two agents.
`
`Thefactorial trial 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 intendedto affect the same
`response variable (a diuretic and another
`anti-hypertensive, for example), or when one
`drug 1s intended to mitigate the side effects
`of the other. These studies can show
`effectiveness (a contribution of each
`componentof the combination) and, in
`addition, provide dosing information for the
`drugs used alone and together.
`A factorial tal employs a parallel fixed-
`dose design with a range of doses of each
`separate drug and someorall combinations
`of these doses. The sample size need not be
`large enoughto distinguish singlecells from
`each other 1n pair-wise compansons because
`all of the data can be used to denve dose-
`responserelationships for the single agents
`and combinations, 1.e., 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
`exceptionsto the ability to rely entirely on
`the response surface analysis in choosing
`dose(s). At the low end of the dose range,if
`the doses used are lower than the recognized
`effective doses of the single agents,it would
`ordinarily be rmportant to have adequate
`evidence that these can be distinguished
`from placebo in a pair-wise comparison. One
`wayto do this in thefactorial study1s to. have
`the lowest dose combination and placebo
`groups be somewhatlarger than other groups;
`another1s to have a separate study of 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 not irreversible
`(cure, death), and if patients.have reasonably
`stable disease. This design suffers, however,
`from the potential problemsof all cross-over
`studies: It can have analytic problemsif there
`are manytreatment withdrawals; it can be
`quite long in duration for an individual
`patient;-and there is often uncertainty about
`carry-overeffects (longer treatment periods
`may minimize this problem), baseline
`comparability after the first period, and
`penod-by-treatmentinteractions. 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 advantagesof the design are that each
`individual receives several different doses so
`that the distribution of individual dose-
`response curves maybe estimated,as well as
`the population average curve, andthat,
`comparedto 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 rising doses,is
`sumilar in concept andlimitations to a
`randomized multiple cross-over dose-
`response study, except that assignmentto
`dose levels is ordered, not random.If most
`patients complete all doses, andif the study
`1s controlled with a parallel placebo group,
`the forced titration study allows a senes of
`comparisonsofan entire randomized group
`given several doses of drug with a concurrent
`placebo,just as the parallel fixed-dose trial
`does. A critical disadvantage18 that, byitself,
`this study design cannot distinguish response
`to increased dose from responseto increased
`time on drug therapy or a cumulative drug
`dosageeffect. It 1s therefore an unsatisfactory
`design w