[Federal Register Volume 59, Number 216 (Wednesday, November 9, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-27723]


[[Page Unknown]]

[Federal Register: November 9, 1994]


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Part VI





Department of Health and Human Services





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Food and Drug Administration



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International Conference on Harmonisation; Dose-Response Information to 
Support Drug Registration; Guideline; Availability; Notice
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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 93D-0194]

 
International Conference on Harmonisation; Dose-Response 
Information to Support Drug Registration; Guideline; Availability

AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.

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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 
Sec. 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 Sec. 10.90(b). Therefore, the 
guideline is not being issued under the authority of current 
Sec. 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 of 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.
    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.

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).

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.

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.

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

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.

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.

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 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.

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 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

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 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 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.

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 a 
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 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.

    Dated: October 25, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-27723; Filed 11-8-94; 8:45 am]
BILLING CODE 4160-01-F