Guideline for Industry

Dose-Response Information

to Support Drug

Registration

ICH-E4

November 1994
TABLE OF CONTENTS

I. INTRODUCTION ............................................... 1

A. Purpose of Dose-Response Information ......................... 1

B. Use of Dose-Response Information in Choosing Doses ............ 2

C. Uses of Concentration-Response Data ......................... 3

D. Problems with Titration Designs ............................... 4

E. Interactions Between Dose-Response and Time .................. 4

II. OBTAINING DOSE-RESPONSE INFORMATION .................... 5

A. Dose-Response Assessment Should Be an Integral Part of Drug

Development .............................................. 5

B. Studies in Life-Threatening Diseases ........................... 5

C. Regulatory Considerations When Dose-Response Data are Imperfect . 6

D. Examining the Entire Database for Dose-Response Information ...... 7

III. STUDY DESIGNS FOR ASSESSING DOSE RESPONSE ............. 7

A. General .................................................. 7

B. Specific Trial Designs ....................................... 9

1. Parallel Dose-Response ............................... 9

2. Cross-over Dose-Response ........................... 11

3. Forced Titration ..................................... 12

4. Optional Titration (Placebo-Controlled Titration to Endpoint) ... 12

IV. GUIDANCE AND ADVICE ...................................... 13

V. REFERENCE ................................................. 16
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.

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
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

and individual dose-response information. The design does,

however, risk confounding of time and dose effects and would be

expected to have particular problems in finding dose-response

relationships for adverse effects. Like the forced titration design, it

can be used to study a wide dose range and, with a concurrent

placebo group, can provide clear evidence of effectiveness. It too

may be especially valuable as an early study to identify doses for a

definitive parallel study.
IV. GUIDANCE AND ADVICE

1. Dose response data are desirable for almost all new chemical entities

entering the market. These data should be derived from study designs

that are sound and scientifically based; a variety of different designs can

give valid information. The studies should be well-controlled, using

accepted approaches to minimize bias. In addition to carrying out formal

dose-response studies, sponsors should examine the entire database for

possible dose-response information.

2. The information obtained through targeted studies and analyses of the

entire database should be used by the sponsor to:

a. Identify a reasonable starting dose, ideally with specific

adjustments (or a firm basis for believing none is needed) for

patient size, gender, age, concomitant illness, and concomitant

therapy, reflecting an integration of what is known about

pharmacokinetic and pharmacodynamic variability. Depending on

circumstances (the disease, the drug's toxicity), the starting dose

may range from a low dose with some useful effect to a dose that

is at or near the full-effect dose.

b. Identify reasonable, response-guided titration steps, and the

interval at which they should be taken, again with appropriate

adjustments for patient characteristics. These steps would be

based either on the shape of the typical individual's dose-effect

dose-effect curves (for both desirable and undesirable effects), if

individual dose-response data were available, or if not, on the

shape of the population (group)-average dose-response, and the

time needed to detect a change in these effects. It should be

noted that methodology for finding the population (group)-average

dose-response, at present, is better established than is

methodology for finding individual dose-response relationships.

c. Identify a dose, or a response (desirable or undesirable), beyond

which titration should not ordinarily be attempted because of a lack

of further benefit or an unacceptable increase in undesirable

effects.

3. It is prudent to carry out dose-ranging or concentration-response studies

early in development as well as in later stages in order to avoid failed

Phase 3 studies or accumulation of a database that consists largely of

exposures at ineffective or excessive doses. The endpoints of studies
may vary at different stages of drug development. For example, in

studying a drug for heart failure, a pharmacodynamic endpoint might be

used early (e.g., cardiac output, pulmonary capillary wedge pressure), an

intermediate endpoint might be used later (e.g., exercise tolerance,

symptoms) and a mortality or irreversible morbidity endpoint might be the

final assessment (survival, new infarction). It should be anticipated that

the dose response for these endpoints may be different. Of course, the

choice of endpoints that must be studied for marketing approval will

depend on the specific situation.

4. A widely used, successful, and acceptable design, but not the only study

design for obtaining population average dose-response data, is the

randomized parallel, dose-response study with three or more dosage

levels, one of which may be zero (placebo). From such a trial, if dose

levels are well chosen, the relationship of drug dosage, or drug

concentration, to clinical beneficial or undesirable effects can be defined.

Several dose levels are needed, at least two in addition to placebo, but in

general, study of more than the minimum number of doses is desirable. 

A single dose level of drug versus placebo allows a test of the null

hypothesis of no difference between drug and placebo, but cannot define

the dose-response relationship. Similarly, although a linear relationship

can be derived from the response to two active doses (without placebo),

this approximation is usually not sufficiently informative. Study designs

usually should emphasize elucidation of the dose-response function, not

individual pair-wise comparisons. If a particular point on the curve, e.g.,

whether a certain low dose is useful, becomes an issue, it should be

studied separately.

5. Dose-response data for both beneficial and undesirable effects may

provide information that allows approval of a range of doses that

encompass an appropriate benefit-to-risk ratio. A well-controlled

dose-response study is also a study that can serve as primary evidence

of effectiveness.

6. Regulatory agencies and drug developers should be open to new

approaches and to the concept of reasoned and well-documented

exploratory data analysis of existing or future databases in search of

dose-response data. Agencies should also be open to the use of various

statistical and pharmacometric techniques such as Bayesian and

population methods, modeling, and pharmacokinetic- pharmacodynamic

approaches. However, these approaches should not subvert the

requirement for dose-response data from prospective, randomized,

multi-dose-level clinical trials. Post-hoc exploratory data analysis in
search of dose-response information from databases generated to meet

other objectives will often generate new hypotheses, but will only

occasionally provide definitive assessment of dose-response

relationships.

A variety of data analytical techniques, including increased use of

retrospective population-type analyses, and novel designs (e.g.,

sequential designs) may help define the dose-response relationship. For

example, fixed-dose designs can be reanalyzed as a continuum of dose

levels if doses are refigured on a milligram per kilogram (mg/kg) basis, or

adjusted for renal function, lean body mass, etc. Similarly, blood levels

taken during a dose-response study may allow estimates of

concentration-response relationships. Adjustment of drug exposure

levels might be made on the basis of reliable information on drug-taking

compliance. In all of these cases, one should always be conscious of

confounding, i.e., the presence of a factor that alters both the refigured

dose and response or that alters both blood level and response,

compliance and response, etc.

7. Dose-response data should be explored for possible differences in

subsets based on demographic characteristics, such as age, gender, or

race. To do this, it is important to know whether there are

pharmacokinetic differences among these groups, e.g., due to metabolic

differences, differences in body habitus, or composition, etc.

8. Approval decisions are based on a consideration of the totality of

information on a drug. Although dose-response information should be

available, depending on the kind and degree of effectiveness shown,

imperfections in the database may be acceptable with the expectation

that further studies will be carried out after approval. Thus, informative

dose-response data, like information on responses in special populations,

on long-term use, on potential drug-drug and drug-disease interactions,

is expected, but might, in the face of a major therapeutic benefit or urgent

need, or very low levels of observed toxicity, become a deferred

requirement.

V. REFERENCE

Federal Register. Vol. 59, No. 216, Wednesday, November 9, 1994, pages

55972-55976.