[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]
_______________________________________________________________________
Part VI
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Dose-Response Information to
Support Drug Registration; Guideline; Availability; Notice
=======================================================================
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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