Guideline for Industry
`
`Dose-Response Information
`to Support Drug
`Registration
`
`ICH-E4
`
`November 1994
`
`MYLAN - EXHIBIT 1021
`
`

`
`TABLE OF CONTENTS
`
`INTRODUCTION
`
`Purpose of Dose-Response Information
`
`Use of Dose-Response Information in Choosing Doses
`
`Uses of Concentration-Response
`
`Data
`
`Problems with Titration Designs
`
`Interactions Between Dose-Response and Time
`
`II
`
`OBTAINING DOSE-RESPONSE INFORMATION
`
`Dose-Response Assessment Should Be an Integral Part of Drug
`Development
`
`Studies in Life-Threatening Diseases
`
`Regulatory Considerations When Dose-Response Data are Imperfect
`
`Examining the Entire Database for Dose-Response Information
`
`III
`
`STUDY DESIGNS FOR ASSESSING DOSE RESPONSE
`
`General
`
`Specific Trial Designs
`
`Parallel Dose-Response
`
`Cross-over Dose-Response
`
`Forced Titration
`
`Optional Titration Placebo-Controlled Titration to Endpoint
`
`IV
`
`GUIDANCE AND ADVICE
`
`REFERENCE
`
`11
`
`12
`
`12
`
`13
`
`16
`
`

`
`GUIDELINE FOR INDUSTRY1
`
`DOSE-RESPONSE INFORMATION TO
`SUPPORT DRUG REGISTRATION
`
`INTRODUCTION
`
`Purpose of Dose-Response Information
`
`Knowledge of the relationships among dose drug concentration drug
`and
`concentration in blood and clinical
`response effectiveness
`for the safe and effective
`undesirable effects is important
`use of drugs in
`This information can help identify an appropriate
`individual patients
`starting dose the best way to adjust dosage to the needs of
`particular
`patient and
`dose beyond which increases would be unlikely to provide
`added benefit or would produce unacceptable side effects
`and/or dose-response information is
`Dose-concentration
`concentration-
`used to prepare dosage and administration instructions in product
`In addition knowledge of dose-response may provide an
`labeling
`economical approach to global drug development
`by enabling multiple
`regulatory agencies to make approval decisions from common
`
`1This guideline was developed within the Expert Working Group Efficacy of the
`International Conference on Harmonisation of Technical Requirements for the
`Registration of Pharmaceuticals for Human Use ICH and has been subject
`to
`consultation by the regulatory parties in accordance with the ICH process This
`document has been endorsed by the ICH Steering Committee at Step
`of the ICH
`process March 10 1994 At Step
`of the process the final draft is recommended for
`adoption to the regulatory bodies of the European Union Japan and the USA This
`1994 59 FR 55972
`guideline was published in the Federal Register on November
`and is applicable to both drug and biological products
`In the past guidelines have
`CFR 10.90b which provides for the use
`generally been issued under
`10.90b
`of guidelines to state procedures or standards of general applicability that are not
`legal
`requirements but that are acceptable to FDA The agency is now in the process of
`revising 10.90b Therefore this guideline is not being issued under the authority of
`10.90b and it does not create or confer any rights privileges or benefits for or on
`any person nor does it operate to bind FDA in any way For additional copies of this
`the Executive Secretariat Staff HFD-8 Center for Drug Evaluation
`guideline contact
`and Research 7500 Standish Place Rockville MD 20855 301-594-1012
`An
`electronic version of this guideline is also available via Internet by connecting to the
`CDER FTP server CDVS2.CDER.FDA.GOV using the FTP protocol
`
`

`
`database
`
`Historically drugs have often been initially 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 hypokalemia and other metabolic disturbances with
`This situation has been improved
`thiazide-type diuretics in hypertension
`by attempts to find the smallest dose with
`discernible useful effect or
`maximum dose beyond which no further beneficial effect
`is seen but
`practical study designs do not exist to allow for precise determination of
`these doses Further expanding knowledge indicates that the concepts
`of minimum effective dose and maximum useful dose do not adequately
`for individual differences and do not allow
`account
`comparison at
`various doses of both beneficial and undesirable effects Any given dose
`provides mixture of desirable and undesirable effects with no single
`dose necessarily optimal for all patients
`
`Use of Dose-Response Information in Choosing Doses
`
`in
`
`in choosing the starting dose of
`What
`is most helpful
`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
`judgment about
`the
`relative importance of desirable and undesirable effects
`For example
`relatively high starting dose on or near the plateau of the effectiveness
`dose-response curve might be recommended for
`drug with
`large
`demonstrated separation between its useful and undesirable dose ranges
`or where
`rapidly evolving disease process demands rapid effective
`high starting dose however might be
`poor choice for
`intervention
`small demonstrated separation between its useful and
`drug with
`undesirable dose ranges In these cases the recommended starting
`low dose exhibiting
`dose might best be
`clinically important effect
`fraction of the patient population with the intent to titrate the dose
`even
`starting dose
`upwards as long as the drug is well tolerated Choice of
`might also be affected by potential
`intersubject variability in
`given blood concentration level or by
`pharmacodynamic
`response to
`such as could arise
`anticipated intersubject pharmacokinetic differences
`from nonlinear kinetics metabolic polymorphism or
`for
`high potential
`lower starting
`In these cases
`pharmacokinetic drug-drug interactions
`dose would protect patients who obtain higher blood concentrations
`entirely possible that different physicians and even different regulatory
`the same data would make different choices as to
`authorities looking at
`the appropriate starting doses dose-titration steps and maximum
`recommended dose based on different perceptions of risk/benefit
`
`It
`
`is
`
`

`
`relationships Valid dose response data allow the use of such judgment
`
`In adjusting the dose in an individual patient after observing the response
`to an initial dose what would be most helpful
`is knowledge of the shape
`the same as the
`of individual dose-response curves which is usually not
`population group average dose-response curve Study designs that
`allow estimation of individual dose-response curves could therefore be
`in guiding titration although experience with such designs and
`useful
`their analysis is very limited
`
`to identify to the
`In utilizing dose-response information it
`is important
`of
`extent possible factors that
`lead to differences in pharmacokinetics
`including demographic factors e.g age
`drugs among individuals
`gender race other diseases e.g renal or hepatic failure diet
`therapies or individual characteristics e.g weight body
`concurrent
`habitus other drugs metabolic differences
`
`Uses of Concentration-Response
`
`Data
`
`drug can be safely and effectively given only with blood
`Where
`concentration monitoring the value of concentration-response
`information
`In other cases an established concentration-response
`is obvious
`relationship is often not needed but may be useful
`For ascertaining
`the magnitude of
`the clinical consequences of pharmacokinetic
`such as those due to drug-disease e.g renal failure or
`differences
`for assessing the effects of the altered
`drug-drug interactions or
`of new dosage forms e.g controlled release
`pharmacokinetics
`formulation or new dosage regimens without need for additional clinical
`trial data where such assessment
`is permitted by regional regulations
`studies are obviously
`Prospective randomized concentration-response
`to defining concentration monitoring therapeutic windows but
`critical
`are also useful when pharmacokinetic
`variability among patients is great
`relationship may in principle be
`in that case
`concentration-response
`smaller number of subjects than
`discerned in
`prospective study with
`could the dose-response relationship in
`standard dose-response study
`information does not
`Note that collection of concentration-response
`imply
`that therapeutic blood level monitoring will be needed to administer the
`relationships can be translated
`drug properly Concentration-response
`into dose-response information Concentration-response
`information can
`also allow selection of doses based on the range of concentrations they
`will achieve most
`satisfactory response Alternatively
`likely to lead to
`if the relationships between concentration and observed effects e.g an
`undesirable or desirable pharmacologic effect are defined the drug can
`the need for further
`be titrated according to patient response without
`
`

`
`blood level monitoring
`
`Problems With Titration Designs
`
`study design widely used to demonstrate effectiveness utilizes dose
`titration to some effectiveness or safety endpoint
`Such titration designs
`informative about dose-response
`without careful analysis are usually not
`relationships In many studies there is
`tendency to spontaneous
`is not easily distinguishable from an
`improvement over time that
`increased response to higher doses or cumulative drug exposure This
`recommended dose the highest
`tendency to choose as
`leads to
`dose used in such studies that was reasonably well tolerated
`dose that was well
`Historically this approach has often led to
`in excess
`of what was really necessary resulting in increased undesirable effects
`In some cases
`e.g to high-dose diuretics used for hypertension
`notably where an early answer
`the
`is essential
`
`because it
`approach is acceptable
`titration-to-highest-tolerable-dose
`often requires minimum number of patients
`For example the first
`marketing of zidovudine AZT for treatment of people with acquired
`immune deficiency syndrome AIDS was based on studies at
`high
`lower doses were as effective and far
`dose later studies showed that
`better tolerated The urgent need for the first effective anti-H IV human
`immunodeficiency virus treatment made the absence of dose-response
`reasonable with the condition that
`information at
`the time of approval
`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 individual dose is often intertwined with the
`frequency of dosing In general when the dose interval
`is long compared
`to the half-life of the drug attention should be directed to the
`basis for the chosen dosing interval
`For example
`pharmacodynamic
`there might be
`comparison of the long dose interval regimen with the
`same dose in more divided regimen looking where this is feasible for
`the dose interval and for adverse
`persistence of desired effect
`throughout
`single dose interval
`effects associated with blood level peaks Within
`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
`variety of other
`given dose should be long enough for the
`ways The study period at
`to be realized whether delay is the result of pharmacokinetic or
`full effect
`factors The dose-response may also be different
`pharmacodynamic
`for
`
`in
`
`

`
`morning versus evening dosing Similarly the dose-response
`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 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
`
`Assessment of dose-response should be an integral component of drug
`development with studies designed to assess dose-response an inherent
`part of establishing the safety and effectiveness of
`the drug If
`information is built
`development of dose-response
`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
`
`therapeutic and investigational
`In particular therapeutic areas different
`behaviors have evolved these affect
`the kinds of studies typically carried
`out Parallel dose-response study designs with placebo or
`titration study designs very effective designs typically
`placebo-controlled
`used in studies of angina depression hypertension etc would not be
`acceptable in the study of some conditions
`such as life-threatening
`least if there were effective
`infections or potentially curable tumors at
`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 may lead to recommended doses that deprive
`some patients of the potential benefit of
`drug by inducing toxicity that
`leads to cessation of therapy On the other hand use of
`low possibly
`subeffective doses or of titration to desired effect may be unacceptable
`failure in these cases may represent an opportunity for cure
`as an initial
`
`forever
`
`lost
`
`even for life-threatening diseases drug developers should
`Nonetheless
`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
`tolerated dose or the dose with the largest effect
`diseases the highest
`surrogate marker will not always be the optimal dose Where only
`on
`
`

`
`single dose is studied blood concentration data which will almost always
`show considerable individual variability due to pharmacokinetic
`differences may retrospectively give clues to possible
`concentration-response
`relationships
`
`single dose has been typical of large-scale intervention
`Use of just
`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
`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
`larger population treated
`increase in costs
`with several doses without significant
`
`Regulatory Considerations When Dose-Response Data Are Imperfect
`
`An otherwise
`Even well-laid plans are not
`invariably successful
`well-designed dose-response study may have utilized doses that were
`too high or too close together so that all appear equivalent albeit
`In that case there is the possibility that the lowest
`superior to placebo
`dose studied is still greater than needed to exert the drugs maximum
`an acceptable balance of observed undesired
`effect Nonetheless
`effects and beneficial effects and beneficial effects might make marketing
`at one of the doses studied reasonable This decision would be easiest
`the drug had special value but even if
`of course 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
`goal of every development
`program approval based on data from studies using
`fixed single dose
`defined dose range but without valid dose response information
`or
`might be appropriate where benefit from new therapy in treating or
`serious disease is clear
`preventing
`
`Examining the Entire Database for Dose-Response Information
`
`information from studies specifically
`In addition to seeking dose-response
`the entire database should be examined
`designed to provide it
`The limitations imposed
`effects
`intensively for possible dose-response
`by certain study design features should of course be appreciated
`For
`example many studies titrate the dose upward for safety reasons As
`most side effects of drugs occur early and may disappear with continued
`this can result
`spuriously higher rate of undesirable effects
`treatment
`at the lower doses Similarly in studies where patients are titrated to
`desired response those patients relatively unresponsive to the drug are
`more likely to receive the higher dose giving an apparent but misleading
`
`in
`
`

`
`inverted U-shaped dose-response curve Despite such limitations
`clinical data from all sources should be analyzed for dose-related effects
`using multivariate multivariate or other approaches
`even if the analyses
`not definitive conclusions
`can yield principally hypotheses
`For example
`an inverse relation of effect
`to weight or creatinine clearance could reflect
`dose-related covariate relationship If pharmacokinetic
`screening
`small number of steady-state blood concentration
`obtaining
`measurements
`in most Phase
`and Phase
`study patients is carried
`out or if other approaches to obtaining drug concentrations during trials
`relation of effects desirable or undesirable to blood
`are used
`concentrations may be discerned The relationship may by itself be
`or may suggest
`further
`persuasive description of concentration-response
`study
`
`III
`
`STUDY DESIGNS FOR ASSESSING DOSE RESPONSE
`
`General
`
`The choice of study design and study population in dose-response trials
`the therapeutic indication under
`will depend on the phase of development
`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 maximum
`tolerated dose
`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
`
`information is best obtained from trials
`In general useful dose-response
`specifically designed to compare several doses
`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
`is also
`possible in some cases to derive retrospectively
`blood
`relationships from the variable concentrations
`concentration-response
`fixed-dose trial While these analyses are potentially
`attained in
`confounded by disease severity or other patient factors the information
`can be useful and can guide subsequent studies Conducting
`dose-response studies at an early stage of clinical development may
`reduce the number of failed Phase
`trials speeding the drug
`development process and conserving development
`resources
`
`It
`
`

`
`Pharmacokinetic
`
`information can be used to choose doses that ensure
`values and diminish
`adequate spread of attained concentration-response
`or eliminate overlap between attained concentrations
`in dose-response
`trials For drugs with high pharmacokinetic variability
`greater spread of
`doses could be chosen Alternatively the dosing groups could be
`covariates e.g
`individualized by adjusting for pharmacokinetic
`lean body mass or renal function or
`correction for weight
`study could be carried out
`concentration-controlled
`
`As
`practical matter valid dose-response data can be obtained more
`readily when the response is measured by
`continuous or categorical
`variable is relatively rapidly obtained after therapy is started and is
`rapidly dissipated after therapy is stopped e.g blood pressure
`wider range of study designs
`In this case
`analgesia bronchodilation
`can be used and relatively small simple studies can give useful
`information Placebo-controlled
`individual subject
`titration designs typical
`of many early drug development studies for example properly conducted
`analysis that models and estimates the
`and analyzed quantitative
`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
`
`In contrast when the study endpoint or adverse effect
`is delayed
`persistent or irreversible e.g stroke or heart prevention asthma
`treatments with late onset response survival
`prophylaxis arthritis
`treatment of depression titration and simultaneous assessment
`cancer
`of response is usually not possible and the parallel dose-response study
`is 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
`response that can occur
`for
`example with mixed agonist-antagonists
`should be
`Trials intended to evaluate dose- or concentration-response
`well-controlled using randomization and blinding unless blinding is
`unnecessary or impossible to assure comparability of treatment groups
`and to minimize potential patient
`and analyst bias and
`investigator
`should be of adequate size
`
`It
`
`to choose as wide
`range of doses as is compatible with
`is important
`practicality and patient safety to discern clinically meaningful differences
`This is especially important where there are no pharmacologic or
`plausible surrogate endpoints to give initial guidance as to dose
`
`Specific Trial Designs
`
`

`
`number of specific study designs can be used to assess
`dose-response The same approaches can also be used to measure
`intended to be an
`relationships Although not
`concentration-response
`the following approaches have been shown to be useful
`exhaustive list
`ways of deriving valid dose-response information Some designs outlined
`in this guidance are better established than others but all are worthy of
`These designs can be applied to the study of established
`consideration
`clinical endpoints or surrogate endpoints
`
`Parallel Dose-Response
`
`fixed-dose groups the randomized
`Randomization to several
`study is simple in concept and is
`design
`parallel dose-response
`The fixed
`that has had extensive use and considerable success
`dose is the final or maintenance dose patients may be placed
`immediately on that dose or titrated gradually in scheduled
`if that seems safer
`forced titration to it
`In either case the final
`dose should be maintained for
`time adequate to allow the
`dose-response comparison Although including
`placebo group in
`dose-response studies is desirable it
`is not theoretically necessary
`positive slope even without
`in all cases
`placebo group
`drug effect To measure the absolute size
`provides evidence of
`of the drug effect however
`placebo or comparator with very
`is usually needed
`limited effect on the endpoint of interest
`Moreover because
`difference between drug groups and placebo
`unequivocally shows effectiveness
`inclusion of
`placebo group
`study that used doses that were all
`can salvage in part
`too high
`and therefore showed no dose-response slope by showing that
`all doses were superior to placebo
`In principle being able to
`detect
`statistically significant difference in pair-wise comparisons
`between doses is not necessary if
`trend
`statistically significant
`upward slope across doses can be established using all
`the data
`that the lowest doses
`It should be demonstrated however
`is to be recommended
`statistically significant and
`has
`tested if
`clinically meaningful effect
`
`it
`
`The parallel dose-response study gives group mean
`population-average dose-response not
`the distribution or shape
`of individual dose-response curves
`
`It
`
`is all
`
`too common to discover at the end of
`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
`formally planned interim analysis or other multi-stage design
`
`parallel
`
`

`
`might detect such
`range
`
`problem and allow study of the proper dose
`
`to
`
`As with any placebo-controlled trial
`it may also be useful
`include one or more doses of an active drug control
`Inclusion of
`both placebo and active control groups allows assessment of
`distinction between an ineffective
`assay sensitivity permitting
`drug and an ineffective null no test study Comparison of
`dose-response curves for test and control drugs not yet
`common design may also represent more valid and informative
`study than comparison of single
`comparative effectiveness/safety
`doses of the two agents
`
`trial
`
`is
`
`It
`
`to affect
`
`The factorial
`special case of the parallel dose-response
`study to be considered when combination therapy is being
`is particularly useful when both agents are intended
`evaluated
`the same response variable
`diuretic and another
`for example or when one drug is intended to
`anti-hypertensive
`mitigate the side effects of the other These studies can show
`contribution of each component of the
`effectiveness
`combination and in addition provide dosing information for the
`drugs used alone and together
`
`fixed-dose design with
`range of
`trial employs
`factorial
`parallel
`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 be used to derive dose-response
`relationships for the single agents and combinations
`i.e
`These trials therefore can be of
`dose-response surface
`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 doses 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
`these can be
`be important
`to have adequate evidence that
`pair-wise comparison One way to
`distinguished from placebo in
`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
`separate study of the low-dose combination
`the high end of the dose range it may be necessary to
`Also at
`confirm the contribution of each component
`to the overall effect
`
`ID
`
`

`
`Cross-over Dose-Response
`
`randomized multiple cross-over study of different doses can be
`if drug effect develops rapidly and patients return to
`successful
`baseline conditions quickly after cessation of therapy if responses
`irreversible cure death and if patients have reasonably
`are not
`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 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
`The length of the trial can be
`interactions
`period-by-treatment
`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
`several different doses so that the distribution of individual
`dose-response curves may be estimated as well as the population
`average curve and that compared to
`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
`
`receives
`
`Forced Titration
`
`forced titration study where all patients move through series of
`rising doses is similar in concept and limitations to
`randomized
`multiple cross-over dose-response study except
`that assignment
`to dose levels is ordered not random If most patients complete all
`doses and if
`parallel placebo group
`the study is controlled with
`the forced titration
`series of comparisons of an
`study allows
`entire randomized group given several doses of drug with
`fixed-dose trial does
`concurrent placebo just as the parallel
`this study design cannot
`critical disadvantage is that by itself
`distinguish response to increased dose from response to
`increased time on drug therapy or
`cumulative drug dosage
`is therefore an unsatisfactory design when response is
`effect
`Even where
`delayed unless treatment at each dose is prolonged
`is known to be short from
`the time until development of effect
`other data this design gives poor information on adverse effects
`many of which have time-dependent
`characteristics
`tendency
`very common circumstance
`toward spontaneous improvement
`
`It
`
`II
`
`

`
`little
`
`is nonetheless
`will be revealed by the placebo group but
`problem for this design as over time the higher doses may find
`room to show an increased effect This design can give
`reasonable first approximation of both population-average dose
`response and the distribution of individual dose-response
`the cumulative time-dependent drug effect
`relationships if
`minimal and the number of treatment withdrawals is not excessive
`parallel dose-response study this design may use
`Compared to
`fewer patients and by extending the study duration can be used
`reasonable
`wide range of doses again making it
`to investigate
`first study With
`concurrent placebo group this design can
`and may be especially
`provide clear evidence of effectiveness
`valuable in helping choose doses for
`parallel dose-response
`study
`
`is
`
`Optional Titration Placebo-Controlled Titration to Endpoint
`
`they reach
`In this design patients are titrated until
`favorable or unfavorable response defined by
`well-characterized
`This approach is most
`dosing rules expressed in the protocol
`applicable to conditions where the response is reasonably prompt
`such as stroke or death
`and is not an irreversible event
`crude
`analysis of such studies e.g comparing the effects in the
`subgroups of patients titrated to various dosages often gives
`misleading inverted U-shaped curve as only poor responders
`are titrated to the highest dose However more sophisticated
`statistical analytical approaches that correct
`for this occurrence
`modeling and estimating the population and individual
`dose-response relationships appear to allow calculation of valid
`dose-response information Experience in deriving valid
`limited It
`dose-response information in this fashion is still
`concurrent placebo group to
`in this design to maintain
`important
`etc
`for spontaneous changes
`correct
`investigator expectations
`Like other designs that use several doses in the same patient
`this
`fixed-dose study of
`design may use fewer patients than
`similar statistical power and can provide both population average
`and individual dose-response
`information The design does
`risk confounding of time and dose effects and would be
`however
`expected to have particular problems in finding dose-response
`relationships for adverse effects
`Like the forced titration design it
`can be used to study wide dose range and with
`concurrent
`placebo group can provide clear evidence of effectiveness
`too
`may be especially valuable as an early study to identify doses for
`definitive parallel study
`
`parallel
`
`by
`
`is
`
`It
`
`12
`
`

`
`IV
`
`GUIDANCE AND ADVICE
`
`Dose response data are desirable for almost all new chemical entities
`entering the market These data should be derived from study designs
`that are sound and scientifically based
`variety of different designs can
`give valid information The studies should be well-controlled using
`approaches to minimize bias In addition to carrying out formal
`accepted
`dose-response studies sponsors should examine the entire database for
`possible dose-response information
`
`The information obtained through targeted studies and analyses of the
`to
`entire database should be used by the sponsor
`
`reasonable starting dose ideally with specific
`Identify
`firm basis for believing none is needed for
`adjustments or
`illness and concomitant
`patient size gender age concomitant
`therapy reflecting an integration of what
`is known about
`and pharmacodynamic
`variability Depending on
`pharmacokinetic
`the disease the drugs toxicity the starting dose
`circumstances
`may range from low dose with some useful effect
`dose that
`to
`is at or near the full-effect dose
`
`Identify reasonable response-guided titration steps and the
`interval at which they should be taken again with appropriate
`These steps would be
`adjustments for patient characteristics
`based either on the shape of the typical
`individuals dose-effect
`dose-effect curves for both desirable and undesirable effects if
`individual dose-response data were available or if not on the
`the population group-average dose-response and the
`shape of
`time needed to detect
`in these effects
`It should be
`change
`noted that methodology for finding the population group-average
`is better established than is
`dose-response at present
`methodology for finding individual dose-response relationships
`
`dose or
`response desirable or undesirable beyond
`Identify
`which titration should n