Wednesday
`November 9} 1994
`
`Part VI
`
`Department of
`Health and Human
`Services
`Food and Drug Administration
`
`International Conference on
`Harmonisation; Dose-Response
`Information to Support Drug Registration;
`Guideline; Availability; Notice
`
`MPI EXHIBIT 1049 PAGE 1
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1049, p. 1 of 6
`
`

`

`5 5 9 7 2
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`Federal Register / Vol. 59, No. 216 / Wednesday, November 9, 1994 / Notices
`
`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
`Food and Drug Administration
`[Docket No. 93D-Q194]
`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
`Administration (FDA) is publishing a
`final guideline entitled “Dose-Response
`Information To Support Drug
`Registration.” The guideline is
`applicable to both drugs and biological
`products. This guideline was prepared
`by the Efficacy Expert Working Group of
`the International Conference on
`Harmonisation of Technical
`Requirements for Registration of
`Pharmaceuticals for Human Use (ICH).
`The guideline describes why dose-
`response information is useful and how
`it should be obtained in the course of
`drug development. This information can
`help identify an appropriate starting
`dose as well as how to adjust dosage to
`the needs of a particular patient. It can
`also identify the maximum dosage
`beyond which any added benefits to the
`patient would be unlikely or would
`produce unacceptable side effects. This
`guideline is intended to help ensure that
`dose response information to support
`drug registration is generated according
`to sound scientific principles.
`EFFECTIVE DATE: November 9,1994.
`ADDRESSES: Submit written comments
`on the guideline to the Dockets
`Management Branch (HFA-305), Food
`and Drug Administration, 12420
`Parklawn Dr., rm. 1-23, Rockville, MD
`20857. Copies of the guideline are
`available from the CDER Executive
`Secretariat 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 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 important initiatives have
`
`been undertaken by regulatory
`authorities and industry associations to
`promote international harmonization of
`regulatory requirements. FDA has
`participated in many meetings designed
`to enhance harmonization and is
`committed to seeking scientifically
`based harmonized technical procedures
`for pharmaceutical development. One of
`the goals of harmonization is to identify
`and then reduce differences in technical
`requirements for drug development.
`ICH was organized to provide an
`opportunity for harmonization
`initiatives to be developed with input
`from both regulatory and industry
`representatives. FDA also seeks input
`from consumer representatives and
`others. ICH is 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
`Welfare, the Japanese Pharmaceutical
`Manufacturers Association, FDA, and
`the U.S. Pharmaceutical Research and
`Manufacturers of America. The ICH
`Secretariat, which coordinates the
`preparation of documentation, is
`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
`Organization, 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 guideline
`entitled “Dose-Response Information To
`Support Drug Registration” should be
`made available for comment. (The
`document is the product of the Efficacy
`Export Working Group of ICH.)
`Subsequently, the draft guideline was
`made available for comment by the
`European Union 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 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 is publishing a
`final guideline entitled “Dose-Response
`Information To Support Drug
`Registration.” It is 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 kinds of studies
`that can obtain such information, and
`gives specific guidance to manufacturers
`on the kinds of 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 is now
`in the process of revising § 10.90(b).
`Therefore, the guideline is not being
`issued under the authority of current
`§ 10.90(b), 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.
`As with all of FDA’s guidelines, the
`public is encouraged to submit written
`comments with new data or other new
`information pertinent to this guideline.
`The comments in the docket will be
`periodically reviewed, and where
`appropriate, the guideline will be
`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 comments are to be submitted,
`except the individuals may submit one
`copy. Comments are to be identified
`with the docket number found in
`brackets in the heading of this
`document. The guideline and received
`comments may be seen in the office
`above between 9 a.m. and 4 p.m.,
`Monday through Friday.
`The text of the final guideline follows:
`Dose-Response Information to Support Drug
`Registration
`I. Introduction
`Purpose o f Dose-Response Information
`Knowledge of the relationships among
`dose, drug concentration in blood, and
`clinical response (effectiveness and
`undesirable effects) is important for the safe
`and effective use of drugs in individual
`patients. This information 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 increases
`would be unlikely to provide added benefit
`or would produce unacceptable side effects.
`Dose-concentration, concentration- and/or
`dose-response information is used to prepare
`dosage and administration instructions in
`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.
`
`.
`
`MPI EXHIBIT 1049 PAGE 2
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1049, p. 2 of 6
`
`

`

`Federal Register 7 Vol. 59, No. 216 / Wednesday, November 9, 1994 / Notices
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`5 5 9 7 3
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`Historically, drugs have often been initially-
`marketed at what were later recognized as
`excessive doses (i.e., dosés 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 thiazide-type
`diuretics in hypertension). This situation has
`been improved by attempts to find the
`smallest dose with a discernible useful effect
`or a 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
`account for individual differences and do not
`allow a comparison, at various doses, of both
`beneficial and undesirable effects. Any given
`dose provides a mixture of desirable and
`undesirable effects, with no single dose,
`necessarily optimal for all patients.
`Use o f Dose-Response Information in
`Choosing Doses
`What is most helpful in choosing the
`starting dose of a drug is knowing the shape
`and location of the population (group)
`average dose-response curve for both
`desirable and undesirable effects. Selection
`of dose is best based on that information,
`together with a judgment about the relative
`importance 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 evolving disease process demands
`rapid effective intervention. A high starting
`dose, however, might be a poor choice for a
`drug with a small demonstrated separation
`between its useful and undesirable dose
`ranges. In these cases, the recommended
`starting dose might best be a low dose
`exhibiting a clinically important effect in
`even a fraction of the patient population,
`with the intent to titrate the dose upwards as
`long as the drug is well tolerated. Choice of
`a starting dose might also be affected by
`potential intersubject variability in
`pharmacodynamic response to a given blood
`concentration level, or by anticipated
`intersubject pharmacokinetic differences,
`such as could arise from nonlinear kinetics,
`metabolic polymorphism, or a high potential
`for pharmacokinetic drug-drug interactions.
`In these cases, a lower starting dose would
`protect patieûts who obtain higher blood
`concentrations. It is entirely possible that
`different physicians and even different
`regulatory authorities, looking at the same
`data, would make different choices as to the
`appropriate starting doses, dose-titration
`steps, and maximum recommended dose,
`based on different perceptions of risk/benefit
`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 of individual dose-
`response curves, which is usually not the
`same as the population (group) average dose-.
`
`response curve. Study designs that allow
`estimation of individual dose-response
`curves could therefore be useful in guiding
`titration, although experience with such
`designs and their analysis is very limited.
`In utilizing dose-response information, it is
`important to identify, to the extent possible,
`factors that lead to differences in
`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 (e.g.,
`weight, body habitus, other drugs, metabolic
`differences).
`Uses o f Concentration-Response Data
`Where a drug can be safely and effectively
`given only with blood concentration
`monitoring, the value of concentration-
`response information is obvious. In other
`cases, an established concentration-response
`relationship is often not needed, but may be
`useful: (1) For ascertaining the magnitude of
`the clinical consequences of pharmacokinetic
`differences, such as those due to drug-disease
`(e.g, renal failure) or drug-drug interactions;
`pr (2) for assessing the effects of the altered
`pharmacokinetics of new dosage forms (e.g.,
`controlled release formulation) or new
`dosage regimens without need for additional
`clinical trial data, where such assessment is
`permitted by regional regulations.
`Prospective randomized concentration-
`response studies are obviously critical to
`defining concentration monitoring
`therapeutic “windows,” but are also useful
`when pharmacokinetic variability among
`patients is great; in that case, a concentration-
`response relationship may in principle be
`discerned in a prospective study with a
`smaller number of subjects than could the
`dose-response relationship in a standard
`dose-response study. Note that collection of
`concentration-response information does not
`imply that therapeutic blood level
`monitoring will be needed to administer the
`drug properly. Concentration-response
`relationships can be translated into dose-
`response information. Concentration-
`response information can also allow selection
`of doses (based on the range of
`concentrations they will achieve) most likely
`to lead to a satisfactory response.
`Alternatively, if the relationships between
`concentration and observed effects (e.g., an
`undesirable or desirable pharmacologic
`effect) are defined, the drug can be titrated
`according to patient response without the
`need for further blood level monitoring.
`Problems With Titra tion Designs
`A study design widely used to demonstrate
`effectiveness utilizes dose titration to some
`effectiveness or safety endpoint. Such
`titration designs, without careful analysis, are
`usually not informative about dose-response
`relationships. In many studies, there is a
`tendency to spontaneous improvement over
`time that is not easily distinguishable from
`an increased response to higher doses or
`cumulative drug exposure. This leads to a
`tendency to choose, as a recommended dose,
`the highest dose used in such studies that
`was reasonably well tolerated. Historically,
`this approach has often led to a dose that was
`
`well in excess of what was really necessary,
`resulting in increased undesirable effects,
`e.g., to high-dose diuretics used for
`hypertension. In some cases, notably where
`an early answer is essential, the titration-to-
`highest-tolerable-dose approach is
`acceptable, because it often requires a
`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 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 information at the time of approval
`reasonable (with the condition that more data
`were to be obtained after marketing), but in
`less urgent cases this approach is
`discouraged.
`Interactions Between Dose-Response and
`Time
`The choice of the size of an 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
`pharmacodynamic basis for the chosen
`dosing interval. For example, there might be
`a comparison of the long dose interval
`regimen with the same dose in a more
`divided regimen, looking, where this is
`feasible, for persistence of desired effect
`throughout the dose interval and for adverse
`effects associated with blood level peaks.
`Within a single dose interval, the dose-
`response relationships at peak and trough
`blood levels may differ and the relationship
`could depend on the dose interval chosen.
`Dose-response studies should take time'
`into account in a variety of other ways. The
`study period at a given dose should be long
`enough for the full effect to be realized,
`whether delay is the result of
`pharmapokinetic or pharmacodynamic
`factors. The dose-response may also be
`different for 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 Assessm ent Should Be an
`Integral Part o f 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 ,
`development of dose-response information is
`built into the development process it can
`usually be accomplished with no loss of time
`and minimal extra effort compared to
`development plans that ignore dose-
`response.
`Studies in Life-Threatening Diseases
`In particular therapeutic areas, different
`therapeutic and investigational behaviors
`
`MPI EXHIBIT 1049 PAGE 3
`
`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1049, p. 3 of 6
`
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`5 5 9 7 4
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`Federal Register / Vol. 59» No. 216 / Wednesday» November 9, 1994 / Notices
`
`have evolved; these affect the kinds of
`studies typically earned 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 in the study of
`some conditions, such as life-threatening
`infections or potentially curable tumors, at
`least if there were effective treatments
`known. Moreover, because in those
`therapeutic areas- considerable 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 a 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 maybe
`unacceptable, as an initial failure in these
`cases may represent an opportunity for cure
`forever lost.
`Nonetheless, even for life-threatening
`diseases, drug developers should always be
`weighing the gains and disadvantages of
`varying regimens and considering how best
`to 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 marker will not
`always be the optimal dose. Where only a
`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.
`Use of just a single dose has been typical
`of large-scale intervention studies (e.g,, post-
`myocardial infarction studies) because of the
`large sample sizes needed. In planning an
`intervention study» the potential advantages
`of studying, more than a single dose should
`be considered. In some cases, it may be
`possible to simplify the study by collecting
`less.information on each patient, allowing,
`study of a larger population treated with
`several doses without significant increase in
`costs.
`Regulatory Considerations When Dose-
`Response Data Are Imperfect
`Even well-laid plans are not invariably
`successful. An otherwise well-designed dose-
`response study may have utilized doses that
`were too high, or top close together, so that
`all appear equivalent (albeit superior to
`placebo). In that case, there is die possibility
`that the lowest dose studied is still greater
`than needed to exert the drag’s maximum
`effect Nonetheless, an acceptable balance of
`observed undesired effects and beneficial
`effects might make marketing at one of die
`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 studies that pardy defined the proper
`dose range, further dose-finding might be
`pursued in the postmarketing period.
`Similarly, although seeking dose response
`data should be a goal of every development
`program, approval based on data from studies
`using a fixed single dose or a defined, dose
`
`range (but without valid dose response
`information) might fee appropriate where
`benefit from a new therapy in treating or
`preventing a serious disease is clear.
`Exam ining the Entire Database fo r Dose-
`Response Information
`In addition to seeking dose-response
`information from studies specifically
`designed to provide it, the entire database
`should be examined intensively for possible
`dose-response effects. The limitations
`imposed 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 treatment, this can
`result in a spuriously higher rate of
`undesirable effects at the lower doses.
`Similarly, in studies where patients are
`titrated to a desired response, those patients
`relatively unresponsive to the drug are more
`likely to receive the higher dose, giving an
`apparent, but misleading, inverted "U-
`shaped” dose-response curve. Despite such
`limitations, clinical data from all sources
`should be analyzed for dose-related effects
`using multivariate or other approaches, even
`if the analyses can yield principally
`hypotheses, not definitive conclusions. For
`example, an inverse relation of effect to
`weight or creatinine clearance could reflect a
`dose-related covariate relationship. If
`pharmacokinetic screening (obtaining, a small
`number of steady-state blood concentration
`measurements in most Phase 2 and Phase 2
`study patients) is carried out, or if other
`approaches to obtaining drug concentrations
`during trials are used, a relation of effects
`(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.
`III. Study Designs for Assessing Dose
`Response
`General
`The choice of study design and study
`population in dose-response trials will
`depend on the phase of development, the
`therapeutic indication under investigation,
`and the severity of the disease in the patient
`population of interest Far example, the lack
`of appropriate salvage therapy for lifer-
`threatening or serious conditions with
`irreversible outcomes may ethically predude
`conduct of studies at doses below the
`maximum tolerated dose. A homogeneous
`patient population will generally allow
`achievement of study objectives with small
`numbers of subjects given each treatment. On
`the other hand, larger, more diverse
`populations allow detection of potentially
`important covariate effects.
`In general, useful dose-response
`information is best obtained from trials
`specifically designed to compare several
`doses. A comparison of results from two or
`more controlled trials with single fixed doses
`might sometimes be informative, e.g., if
`control groups were similar, although even in
`that case, the many across-study differences
`that occur m separate trials usually make this
`approach unsatisfactory. It is also possible in­
`
`some cases to derive, retrospectively, Mood
`concentration-response relationships from
`the variable concentrations attained in a
`fixed-dose trial. While these analyses are
`potentially 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 foiled Phase 3 trials, speeding the
`drug development process and conserving
`development resources.
`Pharmacokinetic informal!km can be used
`to choose doses that ensure adequate spread
`of attained concentration-response values
`and diminish or eliminate overlap between
`attained concentrations in dose-response
`trials; For drugs with high pharmacokinetic
`variability, a greater spread of closes could be
`chosen. Alternatively, the dosing groups
`could be individualized by adjusting for
`pharmacokmetie covariates (e.g., correction
`for weight, lean body mass, or renal function)
`or a concentration-controlled study could be
`carried out.
`As a practical matter, valid dose-response
`data can be obtained more readily when the
`respouse is measured by a continuous or
`categorical variable, is relatively rapidly
`obtained after therapy is started, and is
`rapidly dissipated after therapy is stopped
`(e.g., Mood pressure, analgesia,
`bronchodilatkra). In this case, a wider range
`of study designs 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 and analyzed
`(quantitative analysis that models and
`estimates the population and individual
`dose-response relationships), can give
`guidance for more definitive parallel, fixed-
`dose, dose-response studies or may be
`definitive on their own.
`In contrast, when the study endpoint or
`adverse effect is delayed, persistent, or
`irreversible fe.g., stroke or heart attack
`prevention, asthma prophylaxis, arthritis
`treatments with late onset response, survival
`in cancer, treatment of depression), titration
`and simultaneous assessment of response is
`usually not possible, and the parallel dose-
`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 eurve, where
`higher doses are less effective than lower
`doses, a response that can occur, for example,,
`with mixed agonist-antagonists.
`Trials intended to evaluate dose- or
`concentration-response should be well-
`controiled, using randomization and Winding
`(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 important to choose as wide a range
`of doses as is compatible with practicality
`and patient safety to discern clinically
`meaningful differences. This is especially
`important where there are no pharmacologic
`or plausible surrogate endpoints to give
`initial guidance as to dose,
`
`MPI EXHIBIT 1049 PAGE 4
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
`Ex. 1049, p. 4 of 6
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`Federal Register / Yol. 59, No. 216 / Wednesday, November 9, 1994 / Notices
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`5 5 9 7 5
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`Specific Trial 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 relationships.
`Although not intended to be an exhaustive
`list, the following approaches have been
`shown to be useful ways of deriving valid
`dose-response information. Some designs
`outlined in this guidance are better
`established than others, but all are worthy of
`consideration. These designs can be applied
`to the study of established clinical endpoints
`or surrogate endpoints.
`1. Parallel Dose-Response
`Randomization to several fixed-dose
`groups (the randomized parallel dose-
`response study) is simple in concept and is
`a design that has had extensive use and
`considerable success. The fixed dose is the
`final or maintenance dose; patients may be
`placed immediately on that dose or titrated
`gradually (in a scheduled "forced” titration)
`to it if that seems safer. In either case, the
`final dose should be maintained for a time
`adequate to allow the dose-response
`comparison. Although including a placebo
`group in dose-response studies is desirable,
`it is not theoretically necessary in 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 endpoint of interest is
`usually needed. Moreover, because a
`difference between drug groups and placebo
`unequivocally shows effectiveness, inclusion
`of a placebo group can salvage, in 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 principle, being able
`to detect a statistically significant difference
`in pair-wise comparisons between doses is
`not necessary if a statistically significant
`trend (upward slope) across doses can be
`established using all the data. It should be
`demonstrated, however, that the lowest
`dose(s) tested, if it is to be recommended, has
`a statistically significant and clinically
`meaningful effect.
`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 a parallel dose-response study, that all
`doses were too high (on the plateau of the
`dose-response curve), or that doses did not go
`high enough. A formally planned interim
`analysis (or other multi-stage design) might
`detect such a problem and allow study of the
`proper dose range.
`As with any placebo-controlled trial, it
`may also be useful to include one or more
`doses of an active drug control. Inclusion of
`both placebo and active control groups
`allows assessment of “assay sensitivity,”
`permitting a distinction between an
`ineffective drug and an “ineffective” (null,
`no test) study. Comparison of dose-response
`curves for test and control drugs, not yet a
`common design, may also represent a more
`valid and informative comparative
`effectiveness/safety study than comparison of
`single doses of the two agents.
`
`The factorial trial is a special case of the
`parallel dose-response study to be considered
`when combination therapy is being
`evaluated. It is particularly useful when both
`agents are intended to affect the same
`response variable (a diuretic and another
`anti-hypertensive, for example), or when one
`drug is intended to mitigate the side effects
`of the other. These studies can show
`effectiveness (a contribution of each
`component of the combination) and, in
`addition, provide dosing information for the
`drugs used alone and together.
`A factorial trial employs a parallel fixed-
`dose design with a range of doses of each
`separate drug and some or all combinations
`of these doses. The sample size need not be
`large enough to distinguish single cells from
`each other in pair-wise comparisons because
`all of the data can be used to derive dose-
`response relationships for the single agents
`and combinations, i.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
`exceptions to 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 important to have adequate
`evidence that these can be distinguished
`from placebo in a pair-wise comparison. One
`way to do this in the factorial study is to have
`the lowest dose combination and placebo
`groups be somewhat larger than other groups;
`another is to have a separate study of the
`low-dose combination. Also, at the high 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 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 fi