Guideline for Industry
`
`Dose-Response Information
`to Support Drug
`Registration
`
`ICH-E4
`
`November 1994
`
`MYLAN - EXHIBIT 1037
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Purpose of Dose-Response Information . . . . . . . . . . . . . . . . . . . . . . . . . 1
`
`Use of Dose-Response Information in Choosing Doses . . . . . . . . . . . . 2
`
`Uses of Concentration-Response Data . . . . . . . . . . . . . . . . . . . . . . . . . 3
`
`Problems with Titration Designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`
`Interactions Between Dose-Response and Time . . . . . . . . . . . . . . . . . . 4
`
`II.
`
`OBTAINING DOSE-RESPONSE INFORMATION . . . . . . . . . . . . . . . . . . . . 5
`
`A.
`
`B.
`
`C.
`
`D.
`
`Dose-Response Assessment Should Be an Integral Part of Drug
`Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
`
`Studies in Life-Threatening Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
`
`Regulatory Considerations When Dose-Response Data are Imperfect . 6
`
`Examining the Entire Database for Dose-Response Information . . . . . . 7
`
`III.
`
`STUDY DESIGNS FOR ASSESSING DOSE RESPONSE . . . . . . . . . . . . . 7
`
`A.
`
`B.
`
`General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
`
`Specific Trial Designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`
`1.
`
`2.
`
`3.
`
`4.
`
`Parallel Dose-Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`
`Cross-over Dose-Response . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`
`Forced Titration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
`
`Optional Titration (Placebo-Controlled Titration to Endpoint) . . . 12
`
`IV.
`
`V.
`
`GUIDANCE AND ADVICE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
`
`REFERENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
`
`

`

`GUIDELINE FOR INDUSTRY1
`
`DOSE-RESPONSE INFORMATION TO
`SUPPORT DRUG REGISTRATION
`
`I.
`
`INTRODUCTION
`
`A.
`
`Purpose of Dose-Response Information
`
`Knowledge of the relationships among dose, drug concentration 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
`
`This guideline was developed within the Expert Working Group (Efficacy) of the
`1
`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 4 of the ICH
`process, March 10, 1994. At Step 4 of the process, the final draft is recommended for
`adoption to the regulatory bodies of the European Union, Japan and the USA. This
`guideline was published in the Federal Register on November 9, 1994 (59 FR 55972)
`and is applicable to both drug and biological products. 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, this guideline is not being issued under the authority of
`§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. For additional copies of this
`guideline contact the Executive Secretariat Staff, HFD-8, Center for Drug Evaluation
`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
`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.
`
`B.
`
`Use of 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 patients who obtain higher blood concentrations. It is
`entirely possible that different physicians and even different regulatory
`authorities, looking at the same data, would make different 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).
`
`C.
`
`Uses of 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; or (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.
`
`D.
`
`Problems With Titration 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 (AlDS) 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.
`
`E.
`
`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 pharmacokinetic 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
`
`A.
`
`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
`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.
`
`B.
`
`Studies in Life-Threatening Diseases
`
`In particular therapeutic areas, different therapeutic and investigational
`behaviors have evolved; these affect the kinds of studies typically carried
`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 may be 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.
`
`C.
`
`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 too close together, so that all appear equivalent (albeit
`superior to placebo). In that case, there is the possibility that the lowest
`dose studied is still greater than needed to exert the drug's maximum
`effect. Nonetheless, an acceptable balance of observed undesired
`effects and beneficial effects and beneficial effects might make marketing
`at one of the 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 partly defined the proper dose range, further dose-finding
`might be pursued in the postmarketing period. Similarly, although
`seeking dose response data should be a goal of every development
`program, approval based on data from studies using a fixed single dose
`or a defined dose range (but without valid dose response information)
`might be appropriate where benefit from a new therapy in treating or
`preventing a serious disease is clear.
`
`D.
`
`Examining the Entire Database for 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 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 3 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
`
`A.
`
`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. 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. 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 in
`separate trials usually make this approach unsatisfactory. It is also
`possible in some cases to derive, retrospectively, blood
`concentration-response relationships from the variable concentrations
`attained in a fixed-dose trial. While these analyses are potentially
`confounded by disease severity or 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 3 trials, speeding the drug
`development process and conserving development resources.
`
`

`

`Pharmacokinetic information can be used to choose doses that ensure
`adequate spread of attained concentration-response values and diminish
`or eliminate overlap between attained concentrations in dose-response
`trials. For drugs with high pharmacokinetic variability, a greater spread of
`doses could be chosen. Alternatively, the dosing groups could be
`individualized by adjusting for pharmacokinetic 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 response 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., blood pressure,
`analgesia, bronchodilation). 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 (e.g., stroke or heart 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 curve, where higher
`doses are less effective than lower doses, a response that can occur, for
`example, with mixed agonist-antagonists.
`Trials intended to evaluate dose- or concentration-response should be
`well-controlled, using randomization and blinding (unless blinding is
`unnecessary or impossible) to assure comparability of treatment groups
`and to 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.
`
`B.
`
`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 first period, and
`period-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 incomplete block designs.
`
`The advantages of the design are that each individual 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 series of
`rising 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 random. If most patients complete all
`doses, and if the study is controlled with a parallel placebo group,
`the forced titration study allows a series of comparisons of an
`entire randomized group given several doses of drug with a
`concurrent placebo, just as the parallel fixed-dose trial does. A
`critical disadvantage is that, by itself, this study design cannot
`distinguish response to increased dose from response to
`increased time on drug therapy or a cumulative drug dosage
`effect. It is therefore an unsatisfactory design when response is
`delayed, unless treatment at each dose is prolonged. Even where
`the time until development of effect is known to be short (from
`other data), this design gives poor information on adverse effects,
`many of which have time-dependent characteristics. A tendency
`toward spontaneous improvement, a very common circumstance,
`
`

`

`will be revealed by the placebo group, but is nonetheless a
`problem for this design, as over time, the higher doses may find
`little room to show an increased effect. This design can give a
`reasonable first approximation of both population-average dose
`response and the distribution of individual dose-response
`relationships if the cumulative (time-dependent) drug effect is
`minimal and the number of treatment withdrawals is not excessive.
`Compared to a parallel dose-response study, this design may use
`fewer patients, and by extending the study duration, can be used
`to investigate a wide range of doses, again making it a reasonable
`first study. With a concurrent placebo group this design can
`provide clear evidence of effectiveness, and may be especially
`valuable in helping choose doses for a parallel dose-response
`study.
`
`4.
`
`Optional Titration (Placebo-Controlled Titration to Endpoint)
`
`In this design, patients are titrated until they reach a
`well-characterized favorable or unfavorable response, defined by
`dosing rules expressed in the protocol. This approach is most
`applicable to conditions where the response is reasonably prompt
`and is not an irreversible event, such as stroke or death. A crude
`analysis of such studies, e.g., comparing the effects in the
`subgroups of patients titrated to various dosages, often gives a
`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, by
`modeling and estimating the population and individual
`dose-response relationships, appear to allow calculation of valid
`dose-response information. Experience in deriving valid
`dose-response information in this fashion is still limited. It is
`important, in this design, to maintain a concurrent placebo group to
`correct for spontaneous changes, investigator expectations, etc.
`Like other designs that use several doses in the same patient, this
`design may use fewer patients than a parallel fixed-dose study of
`similar statistical power and can provide both population average