55972
`
`Federal Register. / Vol. 59, No. 216 / Wednesday November 9, 1994 / Notices
`
`DEPARTMENT OF. 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
`Admm1stration (FDA) is publishing a
`finalgmdeline entitled "Dose-Response
`Information To Support Drug
`Registration." The gmdeline is
`applicable to both drugs and biological
`products. This gmdeline was..prepared
`by the Efficacy Expert Workmg Group of
`the International Conference on
`Harmonisation of Technical
`Reqmrements for Registration of
`Pharmaceuticals for Human Use (ICH).
`The gmdeline describes why dose­
`response mformation is useful and how
`it should be obtamed m the course of
`drug develc;>pment. This mformation can
`help identify an appropnate starting
`dose as well as how to adjust dosage to
`the needs of a particular patient. It can
`also identify the maximum dosage
`bey.ond which any added benefits to the
`patient would be unlikely or would
`produce unacceptable side effects. This
`gmdeline is mtended to help ensure that
`dose response mformation to support
`drug registration is generated according
`to sound scientific pnnciples.
`EFFECTIVE DATE: November 9, 1994.
`ADDRESSES: Submit written comments
`on the gmdeline to the Dockets
`Management Branch (HFA-305), Food
`and Drug Admmistration, 12420
`ParklawnDr., rm. 1-23, Rockville, MD
`20857 Copies of the gmdeline are
`available from the CDER Executive
`Secretanat Staff (HFD-8), Center for
`Drug Evaluation and Research, Food
`and Drug Administration, 7500 Standish
`Pl., Rockville, MD 20855.
`FOR FURTHER INFORMATION CONTACT:
`Regarding the gmdeline: Robert
`Temple, Center for Drug Evaluation
`and Research (HFD-100), Food and
`Drug Admmistration, 5600 Fishers
`Lane, Rockville, MD 20857 301­
`443-4330.
`Regarding ICH: Janet Showalter,
`Office· of Health Affairs (HFY-1),
`Food and Drug Admmistration,
`5600 Fishers Lane, Rockville, MD
`20857 301-443-1382.
`SUPPLEMENTARY INFORMATION: In recent
`years, many important mitiatives have
`
`been undertaken by regulatory
`authorities and mdustry associations to
`promote mternatiomi.l harmonization of
`regulatory reqmrements. FDA has
`participated m many meetings designed
`to enhance harmonization and 1s
`committed to seekmg scientifically
`based harmonized technical procedures
`for pharmaceutical development. One of
`the goals of harmonization 1s to identify
`and then reduce differences m technical
`reqmrements for drug development.
`ICH was organized to provide an
`opportunity for harmomzation
`mitiatives to be developed with mput
`from both regulatory and mdustry
`representatives. FDA also seeks mput
`from consumer-representatives and
`others. ICH 1s concerned with
`harmonization of technical
`reqmrements 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
`Welfare, the Japanese Pharmaceutical
`Manufacturers Association, FDA, and
`the U.S. Pharmaceutical Research and
`Manufacturers of Amenca. The ICH
`Secretanat, which coordinates the
`preparation of documentation, is
`provided by the International
`Federation of Pharmaceutical
`Manufacturers Associations (IFPMA).
`The ICH Steenng Committee includes
`representatives from each of the ICH
`sponsors and IFPMA, as well as
`observers from the World Health
`Orgaruzation, the Canadian Health
`Protection Branch, and the European
`Free Trade Area.
`At a meeting held on March 8, 9, and
`10, 1993, the ICH Steering Committee
`agreed that the draft tripartite gmdeline
`entitled "Dose-Response Information To
`Support Drug Registration" should be
`made available for comment. (The
`document 1s the product of the Efficacy
`Export Working Group of ICH.)
`Subsequently the draft gmdeline was
`made available for comment by the
`European Umon and Japan, as well as
`by FDA (see 58 FR 37402, July 9, 1993).
`in accordance with their consultation
`procedures. The comments were
`analyzed and the gmdeline was revised
`as necessary. At a meeting held on
`March 10, 1994, the ICH Steering
`Committee agreed that this final
`gmdeline should be published.
`With this notice, FDA is publishmg a
`final gmdeline entitled "Dose-Response
`Information To Support Drug
`Registration." It 1s applicable to both
`drugs and b10log1cal products. This
`guideline has been endorsed by all ICH
`
`sponsors. The gmdeline describes tlie
`value and uses of dose-response
`mformation and the kinds of studies
`that can obtain such information, and
`gives specific guidance to manufacturers
`on the kinds of mformation they should
`obtain.
`In the past, gmdelines have generally
`been issued under§ 10.90(b) (21 CFR
`-10.90(b)), which provides for the use of
`gmdelines to state procedures or
`standards of general '!,pplicability that
`are not legal reqmrements but that are
`acceptable to FDA. The agency is now
`in the proce:,s ofrevismg § 10.90(b).
`Therefore, the gmdeline is not bemg
`issued under the authority of current
`§ 10.90(b), and it does not create or
`confer any nghts, pnvileges, or benefits
`for or on any person, nor does it operate
`to bmd FDA m any way.
`As with all ofFDA's gmdelines, the
`public is encouraged to submit written
`comments with new data or other new
`information pertinent to this gmdeline.
`The comments in the docket will be
`penodically reviewed, and where
`appropnate, the gmdeline will be
`amended. The public will be notified1of
`any such amendments through a notice
`in the Federal Register.
`Interested persons may at any time,
`submit written comments on the.
`gmdeline to the Dockets Management
`Branch (address above). Two copies of
`any comments are to be submitted,
`except the mdividuals may submit one
`copy. Comments are to be identified
`with the docket number found in
`brackets in the heading of this
`document. The gmdeline and received
`comments may be seen m the office
`above between 9 a.m. and 4 p.m.,
`Monday through·Fnday.
`The text of the fmal gmdeline follows:
`Dose-Response Information to Support Drug
`RegIStration
`I. Introduction
`Purpose ofDose-Response Information
`Knowledge of the relationships among
`dose, drug concentration m blood, and
`climcal response (effectiveness and
`undesirable effects) 1s important for the safe
`and effective use of drugs m mdiv1dual
`patients. This mformation can help identify
`an appropriate starting dose, the best way to
`adjust dosage to the needs of a particular
`patient, and a dose beyond which mcreases
`would be unlikely to provide added benefit
`or would produce unacceptable side effects.
`Dose-concentration, concentration- and/or
`dose-response mformation 1s used to prepare
`dosage and admm1stration mstructions m
`product labeling. 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.
`
`MYLAN - EXHIBIT 1009
`
`

`
`Federal Register / Vol. 59, No. 216 I Wednesday November 9, 1994 l Notices
`
`55973
`
`Histoncally, drugs have often been mitially
`marketed at what were later recognized as
`excessive doses (i.e., doses well onto the
`plateau of the dose-response curve for the
`des1rBd effect), sometimes with adverse
`consequences (e.g., hypokalem1a and other
`metabolic disturbances with tlirnzide-type
`diuretics m hypertens10n). This situation has
`been improved by attempts to find the
`smallest dose with a discernible useful effect
`or a maxunum dose beyond which no further
`beneficial effect 1s seen, but practical study
`designs do not exist to allow for precise
`determmation of these doses. Further,
`expanding knowledge mdicates that the
`concepts ofmmunum effective dose and
`maximum useful dose do not adequately
`account for mdiv1dual differences and do not
`allow a companson, at various doses, of both
`beneficrnl and undesirable effects. Any given
`dose provides a mixture of desirable and
`undesirable effects, with no smgle dose
`necessarily optimal for all patients.
`Use ofDose-Response Information m
`Choosing Doses
`what 1s most helpful m choosmg the
`starting dose of a drug 1s knowmg 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 mformation,
`together with a Judgment about the relative
`unportance of desirable and undesirable
`effects. For example, a relatively high starting
`dose (on or near the plateau of the
`effectiveness dose-response curve) might be
`recommended for a drug with a large
`demonstrated separation between its useful
`and undesirable dose ranges or where a
`rapidly evolvmg disease process demands
`rapid effective intervention. A high starting
`dose, however, might be a poor chmce for a
`drug with a small demonstrated separation
`between its useful and undesirable dose
`ranges. In these cases, the recommended
`starting dose might best be a low dose
`exhibiting a clinically unportant effect m
`even a fraction of the patient population,
`with the mtent to titrate the dose upwards as
`long as the drug 1s well tolerated. Chmce of
`a starting dose might also be affected by
`potential mtersub1ect varrnbility m
`pharmacodynam1c response to a given blood
`concentration level, or by anticipated
`mtersub1ect pharmacokmetic differences,
`such as could arise from nonlinear kmetics,
`metabolic polymorphism, or a high potential
`for pharmacolonetic drug-drug mteractions.
`In these cases, a lower starting dose would
`protect patients who obtam higher blood
`concentrations. It 1s entirely possible that
`different phys1c1ans and even different
`regulatory authorities, lookmg at the same
`data, would make different choices as to the
`appropnate starting doses, dose-titration
`steps, and maxunum recommended dose,
`based on different perceptions of risk/benefit
`relationships. Valid dose response data allow
`the use of such Judgment.
`In adjusting the dose m an mdiv1dual
`patient after observmg the response to an
`mitial dose, what would be most helpful 1s
`knowledge of the shape of individual dose­
`response curves, which 1s usually not the
`same as the population (group) average dose­
`
`response curve. Study designs that allow
`estimation of individual dose-response
`curves could therefore be useful m gmding
`titration, although expenence with such
`designs and their analysis 1s very limited.
`In utilizmg dose-response mformation, it 1s
`important to identify, to the extent possible,
`factors that lead to differences m
`pharmacokmetics of drugs among
`mdiv1duals, mcluding demographic factors
`(e.g., age, gender, race), other diseases (e.g.,
`renal or hepatic failure), diet, concurrent
`therapies, or-mdiv1dual characteristics (e.g.,
`wBight, body habitus, other drugs, metabolic
`differences).
`Uses ofConcentration-Response Data
`Where a drug can be safely and effectively
`given only with blood concentration
`monitormg, the value of concentration­
`response mformation 1s obvious. In other
`cases, an established concentration-response
`relationship 1s often not needed, but may be
`useful: (1) For ascertammg the magnitude of
`the clinical consequences of pharmacokmetic
`differences, such as those due to drug-disease
`(e.g. renal failure) or drug-drug mteractions;
`or (2) for assessmg the effects of the altered
`pharmacokmetics of new dosage forms (e.g.,
`controlled release formulation) or new
`dosage regimens without need for additional
`climcal trial data, where such assessment 1s
`permitted by regional regulations.
`Prospective randomized concentration­
`response studies are obviously critical to
`definmg concentration monitonng
`therapeutic "wmdows, but are also useful
`when pharmacokmetic varrnbility among
`patients 1s great; m that case, a concentration­
`response relationship may m pnnc1ple be
`discerned ma prospective study with a
`smaller number of sub1ects than could the
`dose-response relationship m a standard
`dose-response study. Note that collection of
`concentration-response mformation does not
`imply that therapeutic blood level
`monitormg will be needed to administer the
`drug properly. Concentration-response
`relationships can be translated mto dose­
`response mfonnation. Concentration­
`response mformation can also allow selection
`of doses (based on the range of
`concentrations they will achieve) most likely
`to lead to a satisfactory response.
`Alternative\y, if the relationships between
`concentration and observed effects (e.g., an
`undesirable or desirable pharmacolog1c
`effect) are defined, the drug can be titrated
`according to patient response without the
`need for further blood level monitormg.
`Problems With Titration Designs
`A study desJgn widely used to demonstrate
`effectiveness utilizes dose titration to some
`effectiveness or safety endpomt. Such
`titration designs, without careful analysis, are
`usually not mformative about dose-response
`relationships. In many studies, there 1s a
`tendency to spontaneous unprovement over
`time that 1s not easily distinguishable from
`an mcreased response to higher doses or
`cumulative drug exposure. This leads to a
`tendency to choose, as a recommended dose,
`the highest dose used m such studies that
`was reasonably well tolerated. Histoncally,
`this approach has often led to a dose that was
`
`well m excess of what was really necessary,
`resulting m mcreased undesirable effects,
`e.g., to high-dose diuretics used for
`hypertension. In some cases, notably where
`an early answer 1s essential, the titration-to­
`hlghest-tolerable-dose approach 1s
`acceptable, because it often requires a
`mm1mum number of patients. For example,
`the first marketing of z1dovudine (AZT) for
`treatment of people with acquired immune
`deficiency syndrome (AIDS) was based on
`studies at a high dose; later studies showed
`that lower doses were as effective and far
`better tolerated. The urgent need for the first
`effective anti-HIV (human immunodeficiency
`virus) treatment made the absence of dose­
`response mformation at the time of approval
`reasonable (with the condition that more data
`were to be obtamed after marketing), but m
`less urgent cases this approach 1s
`discouraged.
`Interactions Between Dose-Response and
`
`Time
`
`The chmce of the size of an individual
`dose 1s often mtertwmed with the frequency
`of dosmg. In general, when the dose mterval
`1s Jong compared to the half-life of the drug,
`attention should be directed to the
`pharmacodynam1c basis for the chosen
`dosmg mterval. For example, there might be
`a comparison of the long dose mterval
`regimen with the same dose m a more
`divided regimen, lookmg, where this 1s
`feasible, for persistence of desired effect
`throughout the doseinterval and for adverse
`effects assocrnted with blood level peaks.
`Withm a smgle dose mterval, the dose­
`response relationships at peak and trough
`blood levels may differ and the relationship
`could,depend on the dose uiterval chosen.
`Dose-response studies should take time
`mto account m a variety of other ways. The
`study penod at a given dose should be long
`enough for the full-effect to be realized,
`whether delay 1s the result of
`pharmacokmetic or pharmacodynam1c
`factors. The dose-response may also be
`different for mommg versus evening dosmg.
`Similarly, the dose-response relationship
`durmg early dosmg may not be the same as
`m the subsequent mamtenance dosmg
`penod. Responses could also be related to
`cumulative dose, rather than daily dose, to
`duration of exposure (e.g., tachyphylax1s,
`tolerance, or hysteresis) or to the
`relationships of dosmg to meals.
`II. Obta1mng Dose-Response Information
`Dose-Response Assessment Should Be an
`
`Integral Part ofDrug Development
`
`Assessment of dose-response should be an
`mtegral component of drug development
`with studies designed to assess dose­
`response an mherent part of establish mg the
`safety and effectiveness of.the drug. If
`development of dose-response mformation 1s
`built mto the development process it can
`usually be accomplished with no loss of time
`and mm1mal extra effort compared to
`development plans that ignore dose­
`response.
`Studies in Life-Threatening Diseases.
`In particular therapeutic areas, .different
`
`therapeutic and mvestigational behaviors
`
`
`

`
`55974
`
`Federal Register / Vol. 59, No 216 / Wednesday November 9, 1994 / Notices
`
`have evolved; tb~se affect the lands of
`studies typically earned out. Parallel dose­
`response study designs with placebo, or
`placebo-controlled titration study designs
`(very effective designs, typically used m
`studies of angma, depression, hypertension,
`etc.) would not be acceptable m the study of
`some conditions, such as life-threatemng
`mfections or potentially curable tumors, at
`least if there were effective treatments
`known. Moreover, because m 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 depnve some patients of the potential
`benefit of a drug by inducmg toxicity that
`leads to cessation of therapy. On the other
`hand, use of low, possibly imbeffective,
`doses, Ol' of titration to desired effect may be
`unacceptable, as an ·initial failure m these
`cases may represent an opportunity for cure
`forever lost.
`Nonetheless, even for life-threatenmg
`diseases, drug developers should always b\l,
`we1ghmg the gems and disadvantages of
`varymg regimens and cons1dermg how best
`to choose dose, dose-interval and dose­
`escalation steps. Even in indications
`mvolvmg life-threatening diseases, the
`highest tolerated dose, or the dose with the
`largest effect on a surrogate marker will not
`always be the optimal dose. Where only a
`smgle dose 18 studied, blood concentration
`data, which will almost always show
`conSiderable individual variability due to
`pharmacoldnetic differences, may
`retrospectively give clues to possible
`concentration-response relationships.
`Use of just a smgle dose has.been typical
`of large-scale intervention studies (e.g., post­
`myocardial mfarction studies) because of the
`large sample sizes needed. In plannmg an
`intervention study, the potential advantages
`of studying more than a smgle dose should
`be considered. In some cases, it may be
`possible to simplify the study by collecting
`less mfonnation on each patient, allowmg
`study of a larger population treated with
`siiveral doses without significant increase m
`costs.
`Regulatory Considerations When Dose­
`Response Data Are Imperfect
`Even well-laid ·plans are not mvanably
`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 supenor to
`placebo). In that case, there is the possibility
`that the lowest dose studied lB 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 of the
`doses studied reasonable. This dec1S1on
`would be easiest, of course, if the drug had
`special value, but even if it did not, 1n light
`of the studies that partly defined the proper
`dose range, further dose-finding JD1ght be­
`pursued m 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
`mfonnation).migbt be appropriate where
`benefit from a new therapy m treating or
`preventing a senous disease 1s clear.
`Examining the..§ntire Database for Dose­
`Response Information
`In addition to seeking dose-response
`mformation from studies specifically
`designed to provide it, the entire database
`should be exammed mtens1vely for possible
`dose-response effects. The limitations
`imposed by certam 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 treatment; tlus can
`result m a spuriously higher rate of
`undesirable effects at the lower doses.
`Similarly,.m·studies where patients are
`titrated to a desired response, those patients
`relatively unresponsive to the drug are more
`likely to receive the higher dose, givmg an
`apparent, but misleading, mverted "U­
`shaped" dose-response curve. Despite such.
`limitations, climcal data from all sources
`should be analyzed for dose-related effects
`using.multivariate or other approaches, even
`if the analyses can yield prmc1pally
`hypotheses, not definitive conclusions. For
`example, an inverse relation of effect to
`weight or creatinme clearance could reflect a
`dose-related covariate relationship. If
`pharmacoktnetic screenmg (obtB1mng a small
`number of steady-state blood concentration
`
`measurements m most Phase 2 and Phase 3
`
`study patients) 1s earned out, or if other
`
`approaches to obtammg drug concentrations
`
`durmg trials are used, a relation of effects
`
`(desirable or undesirable) to blood
`
`concentrations may be discerned. The
`
`relationslup may by itself be a persuasive
`descnption of concentration-response or may.
`suggest further study.
`m. Study Designs for Assessmg Dose
`Response
`General
`The choice of study design and study
`population m dose-response trials will
`depend on the phase of development, the
`therapeutic mdication under investigation,
`and the severity of the disease 1n the patient
`population of interest. For example, the lack
`of appropriate salvage therapy for life­
`threatening or senous conditions with
`irreversible outcomes may ethically preclude
`conduct of studies at doses below the
`maxunum tolerated dose. A homogeneous
`_patient population will generally allow
`achievement of study obJectives with small
`numbers of subjects given each treatment On
`the other hand, larger, more diverse
`populations allow detection of potentially
`unportant covanate effects.
`In general, usefu dose-response
`
`mformation ls best obtamed from trials
`
`specifically designed to compare several
`
` doses. A comparison.ofresults from two or
`more controlled trials with single fixed doses
`rmght sometimettbe Informative, e.g., if
`control groups were similar, &though even In
`that case, tha many acros&,lltudy differences,
`that occur in separate trials usually make this
`approach WIS3t!sfuctory.-It is also possible In
`
`some cases to denve, retrospectively, blood
`concentration-response relationships from
`the vanable concentrations attamed m a
`fixed-dose tnal. While these analyses are
`potentially confounded by disease severity or
`other patient factors, the mformation can be
`useful and can guide·subsequent studies.
`Conducting dose-response studies at an early
`stage of climcal development may reduce the
`number of failed Phase 3 trials, speeding the
`drug development process and conservmg
`development resources.
`Pharmacokmetic mformation con be used
`to choose doses that ensure adequate spread
`of attamed concentration-response values
`and dimm1sh or elimmate overlap between
`attamed concentrations m dose-response
`tnals. For drugs with high pharmacolanetic
`vanability, a greater spread of doses could be
`chosen. Alternatively, the dosing groups
`could be1.ndividualized by adjusting for
`pharmacokmetic cov,nates (e.g., correction
`for weight lean body mass, or renal function)
`or a concentration-controlled study could be
`earned out.
`As a practical matter, valid dose-response
`data can be obtamed more readily when the
`response ls measured by a continuous or
`categorical vanable, is relatively rapidly
`obtamed after therapy is started, and 1s
`rapidly dissipated after therapy 1s stopped
`(e.g., blood pressure, analgeS1a,
`bronchodilation). In this case, a wider range
`of study de111gns can be used and relatively
`small, sunple studies can give useful
`mfonnation. Placebo-controlled mdiv1dual
`sub1ect titration designs typical of many early
`drug development studies, for example,
`properly conducted and analyzed
`(quantitative analysis that models and
`estimates the population and mdiv1dual
`dose-response relationsh1p_s),.can give
`guidance for more.definitive parallel, fixed­
`dose, dose-response studies or may be
`definitive on their_own.
`In contrast, when the study endpomfor
`adverse effect is delayed, persistent, or
`1rreverslble (e.g., stroke or heart attack
`prevention, asthma prophylBXIs, arthritis
`treatments with late onset response, survival
`m cancer, treatment of depression), titration
`and simultaneous assessment of response 1s
`usually not possible, and the parallel dose­
`response study 1s usually needed. The
`parallel dose-response study also offers
`protection agamst m1ssmg 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, a response that can occur, for.example,
`with mixed agorust-antagomsts.
`Tnals 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 mmlIIlize potential
`patient, investigator, and analyst bias, and
`should be of adequate size
`It 1s important to choose as wide a range·
`of doses as is compatible with .practicality
`and patient safety-to.discern climcally
`meaningful differences. This ls especially
`important where.there are no. phannacologic
`or plausible surrogate.endpomts to give
`11iitial guidance as to dose.
`
`

`
`Federal Register / Vol. 59, No. 216 / Wednesday,_ November 9, 1994 / Notices
`
`55975
`
`Specific Tnal Designs
`A number of specific study designs can be
`used to assess dose-response. The same
`approaches can also be used to measure
`concentration-response relationsh1 ps.
`Although not mtended to be an exhaustive
`list, the following approaches have been
`shown to be useful ways of derivmg valid
`dose-response mformation. Some designs
`outlined m this guidance are better
`established than others, but all are worthy of
`consideration. These designs can be applied
`to the study of established climcal endpomts
`or surrogate endpomts.
`1. Parallel Dose-Response
`Randomization to several fixed-dose
`
`groups (the randomized parallel dose­
`
`response study) 1s simple m concept and 1s
`
`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 seems safer. In either case, the
`final dose should be mamtained for a time
`adequate to allow the dose-response
`comparison. Although including a placebo
`group m dose-respon110 studies 1s desirable,
`it 1s not theoretically necessary m all cases;
`a positive slope, even without a placebo
`group, provides evidence of a drug effect. To
`measure the absolute size of the drug effect,
`however, a placebo or comparator with very
`limited effect on the endpomt of interest 1s
`usually needed..Moreover, because a
`difference between drug groups and placebo
`unequivocally shows effectiveness, mclus1on
`of a placebo group can salvage, m part, a
`study that used doses that were all too high
`and, therefore, showed no dose-response
`slope, by showing that all doses were
`superior to placebo. In prmc1ple, bemg able
`to detect a statistically significant.difference
`m pair-wise compansons between doses 1s
`nQt necessary if a statistically significant
`trend (upward slope) across doses can be
`established usmg 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
`meanmgful effect.
`The parallel dose-response study gives
`
`group mean (population-average) dose­
`
`response, not the distribution or shape of
`
`mdiv1dual dose-response curves.
`
`It is all too common to discover, at the end
`of a parallel dose-response study, that all
`doses were too high (on the plateau of the
`dose-response curve), or that doses did not go
`high enough. A formally planned mtenl!!
`analysis (or other multi-stage design) might
`detect such a problem and allow study of the
`proper dose range.
`As with any placebo-controlled trial, it
`
`may also be useful to include one or more
`
`doses of an active drug control. Inclusion of
`
` both placebo and active control groups
`allows assessment of "assay sensitivity,
`permitting a distinction between an
`meffective drug and an "ineffective" (null,
`no test) study. Companson of dose-response
`curves for test and control drugs, not yet a
`common design, may also represent a more
`valid and informative comparative
`effectiveness/safety study than comparison of
`smgle doses of the two agents.
`
`The factorial trial 1s a special case of the
`parallel dose-response study to be considered
`when combmation therapy 1s bemg
`evaluated. It 1s particularly useful when both
`agents are mtended to affect the same
`response variable (a diuretic and another
`anti-hypertensive, for example), or when one
`drug 1s mtended to mitigate the side effects
`of the other. These studies can show
`effectiveness (a contribution of each
`component of the combmation) and, m
`addition, provide dosmg Information for the
`drugs used alone and together.
`A factorial trial ·employs a parallel fi:Xed­
`dose design with a range of doses of each
`separate drug and some or all combmations
`of these doses. The sample size need not be
`large enough to distinguish smgle cells from
`·each other m pair-wise comparisons because
`all of the data can be used to derive dose­
`response relationships for the smgle agents
`and combmations, 1.e., a dose-response
`surface. These trials, therefore, can be of
`moderate size. The doses and combmations
`that could be approved for marketing might
`not be limited to the actual doses studied but
`might mclude doses and combinations m
`between those studied. There may be some
`exceptions to the ability to rely entirely on
`the response surface analysis in choosmg
`dose(s). At the low end of the dose range, if
`the doses used are lower than the recognized
`effective doses of the smgle agents, it would
`ordinarily be important to have adequate
`evidence that these can be distinguished
`from placeoo in a pa1r-w1se comparison. One
`way to do this m the factorial study 1s to have
`the lowest dose combmation and placebo
`groups be.somewhat larger than other groups;
`another 1s to have a separate study of the
`low-dose combmation. 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 problems of all cross-over
`studies: It can have analytic problems if there
`are many treatment withdrawals; it can be
`quite long m duration for an individual
`patient;.and there Is often uncertainty about
`carry-over effects (longer treatment periods
`may mmim1ze this problem), baseline
`comparability after the first period, and
`penod-by-treatment interactions. The length
`of the trial can be reduced by approaches that
`do not require all patients to receive each
`dose, such as balanced mcomplete block
`designs.
`The advantages of the design are that ea h
`mdiv1dual receives 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 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 nsmg doses, Is
`similar in concept and limitations to a
`randomized multiple cross-over dose­
`response study, except that assignment to
`dose levels is ordered, not r