Guidance for Industry
`
`Exposure-Response Relationships — Study
`Design, Data Analysis, and Regulatory
`Applications
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`April 2003
`CP
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`MPI EXHIBIT 1048 PAGE 1
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`
`

`

`Guidance for Industry
`
`Exposure-Response Relationships — Study
`Design, Data Analysis, and Regulatory
`Applications
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research (CDER)
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
`http://www.fda.gov/cder/guidance/index.htm
`
`or
`
`Office of Communication, Training and Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research (CBER)
`Food and Drug Administration
`1401 Rockville Pike, Rockville, MD 20852-1448
`Voice Information: 800-835-4709 or 301-827-1800
`http://www.fda.gov/cber/guidelines.htm
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`April 2003
`
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`TABLE OF CONTENTS
`
`INTRODUCTION................................................................................................................. 1
`I.
`II. BACKGROUND ................................................................................................................... 2
`III. DRUG DEVELOPMENT AND REGULATORY APPLICATIONS.............................. 2
`A.
`Information to Support the Drug Discovery and Development Processes ...............................3
`B.
`Information to Support a Determination of Safety and Efficacy ..............................................3
`IV. DOSE-CONCENTRATION-RESPONSE RELATIONSHIPS
`AND EFFECTS OVER TIME..................................................................................................... 8
`A. Dose and Concentration-Time Relationships..............................................................................8
`B. Concentration-Response Relationships: Two Approaches .......................................................9
`V. DESIGNS OF EXPOSURE-RESPONSE STUDIES ......................................................... 9
`A. Population vs. Individual Exposure-Response ..........................................................................10
`B. Exposure-Response Study Design ..............................................................................................10
`C. Measuring Systemic Exposure....................................................................................................12
`D. Measuring Response ....................................................................................................................15
`VI. MODELING OF EXPOSURE-RESPONSE RELATIONSHIPS .................................. 16
`A. General Considerations...............................................................................................................17
`B. Modeling Strategy........................................................................................................................17
`VII.
`SUBMISSION INFORMATION: EXPOSURE-RESPONSE STUDY REPORT... 19
`REFERENCES............................................................................................................................ 21
`APPENDIX A: RELATED GUIDANCES .............................................................................. 22
`APPENDIX B: PEDIATRIC DECISION TREE INTEGRATION OF PK-PD .................. 25
`
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`Contains Nonbinding Recommendations
`
`Guidance for Industry1
`
`Exposure-Response Relationships: Study Design, Data Analysis,
`and Regulatory Applications
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`An alternative approach may be used if such approach satisfies the requirements of the applicable statutes
`and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
`implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
`number listed on the title page of this guidance.
`
`I.
`
`INTRODUCTION
`
`This document provides recommendations for sponsors of investigational new drugs (INDs) and
`applicants submitting new drug applications (NDAs) or biologics license applications (BLAs) on
`the use of exposure-response information in the development of drugs, including therapeutic
`biologics. It can be considered along with the International Conference on Harmonisation (ICH)
`E4 guidance on Dose-Response Information to Support Drug Registration and other pertinent
`guidances (see Appendix A).
`
`This guidance describes (1) the uses of exposure-response studies in regulatory decision-making,
`(2) the important considerations in exposure-response study designs to ensure valid information,
`(3) the strategy for prospective planning and data analyses in the exposure-response modeling
`process, (4) the integration of assessment of exposure-response relationships into all phases of
`drug development, and (5) the format and content for reports of exposure-response studies.
`
`This guidance is not intended to be a comprehensive listing of all of the situations where
`exposure-response relationships can play an important role, but it does provide a range of
`examples of where such information may be of value.
`
`FDA's guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`1 This guidance has been prepared by the Exposure-Response Working Group under the Medical Policy
`Coordinating Committee, Center for Drug Evaluation and Research (CDER), in cooperation with the Center for
`Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA).
`
`1
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`Contains Nonbinding Recommendations
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`II.
`
`BACKGROUND
`
`Exposure-response information is at the heart of any determination of the safety and
`effectiveness of drugs. That is, a drug can be determined to be safe and effective only when the
`relationship of beneficial and adverse effects to a defined exposure is known. There are some
`situations, generally involving a very well-tolerated drug with little dose-related toxicity, in
`which the drug can be used effectively and safely at a single dose well onto the plateau part of its
`exposure-response curve, with little adjustment for pharmacokinetic (PK) or other influences in
`individuals. In most situations, however, for more toxic drugs, clinical use is based on weighing
`the favorable and unfavorable effects at a particular dose. Sometimes with such drugs, the doses
`can be titrated to effect or tolerability. In most cases, however, it is important to develop
`information on population exposure-response relationships for favorable and unfavorable effects,
`and information on how, and whether, exposure can be adjusted for various subsets of the
`population.
`
`Historically, drug developers have been relatively successful at establishing the relationship of
`dose to blood concentrations in various populations, thus providing a basis for adjustment of
`dosage for PK differences among demographic subgroups or subgroups with impaired
`elimination (e.g., hepatic or renal disease), assuming systemic concentration-response
`relationships are unaltered. Far less attention has been paid to establishing the relationship
`between blood concentrations and pharmacodynamic (PD) responses and possible differences
`among population subsets in these concentration-response (often called PK-PD) relationships.
`These can be critical, as illustrated by the different responses to angiotensin-converting enzyme
`(ACE) inhibitors in both effectiveness and safety between Black and Caucasian populations.
`
`For the purposes of this guidance, we are using the broad term exposure to refer to dose (drug
`input to the body) and various measures of acute or integrated drug concentrations in plasma and
`other biological fluid (e.g., Cmax, Cmin, Css, AUC). Similarly, response refers to a direct
`measure of the pharmacologic effect of the drug. Response includes a broad range of endpoints
`or biomarkers ranging from the clinically remote biomarkers (e.g., receptor occupancy) to a
`presumed mechanistic effect (e.g., ACE inhibition), to a potential or accepted surrogate (e.g.,
`effects on blood pressure, lipids, or cardiac output), and to the full range of short-term or long-
`term clinical effects related to either efficacy or safety. This exposure-response guidance focuses
`on human studies, but exposure-response information in animal pharmacology/toxicology studies
`is also a highly useful component of planning the drug development process (Peck 1994; Lesko
`2000).
`
`III.
`
`DRUG DEVELOPMENT AND REGULATORY APPLICATIONS
`
`This section describes the potential uses of exposure-response relationships in drug development
`and regulatory decision-making. The examples are not intended to be all-inclusive, but rather to
`illustrate the value of a better understanding of exposure-response relationships. We recommend
`that sponsors refer to other ICH and FDA guidances for a discussion of the uses of exposure-
`response relationships (see Appendix A).
`
`2
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`Contains Nonbinding Recommendations
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`A.
`
`Information to Support the Drug Discovery and Development Processes
`
`Many drugs thought to be of potential value in treating human disease are introduced into
`development based on knowledge of in vitro receptor binding properties and identified
`pharmacodynamic effects in animals. Apart from describing the tolerability and PK of a drug in
`humans, Phase 1 and 2 studies can be used to explore the relationship of exposure (whether dose
`or concentration) to a response (e.g., nonclinical biomarkers, potentially valid surrogate
`endpoints, or short-term clinical effects) to (1) link animal and human findings, (2) provide
`evidence that the hypothesized mechanism is affected by the drug (proof of concept), (3) provide
`evidence that the effect on the mechanism leads to a desired short-term clinical outcome (more
`proof of concept), or (4) provide guidance for designing initial clinical endpoint trials that use a
`plausibly useful dose range. Both the magnitude of an effect and the time course of effect are
`important to choosing dose, dosing interval, and monitoring procedures, and even to deciding
`what dosage form (e.g., controlled-release dosage form) to develop. Exposure-response and PK
`data can also define the changes in dose and dosing regimens that account for intrinsic and
`extrinsic patient factors.
`
`B.
`
`Information to Support a Determination of Safety and Efficacy
`
`Apart from their role in helping design the well-controlled studies that will establish the
`effectiveness of a drug, exposure-response studies, depending on study design and endpoints,
`can:
`
`• Represent a well-controlled clinical study, in some cases a particularly persuasive one,
`contributing to substantial evidence of effectiveness (where clinical endpoints or accepted
`surrogates are studied)
`
`• Add to the weight of evidence supporting efficacy where mechanism of action is well
`understood (e.g., when an effect on a reasonably well-established biomarker/surrogate is used
`as an endpoint)
`
`• Support, or in some cases provide primary evidence for, approval of different doses, dosing
`regimens, or dosage forms, or use of a drug in different populations, when effectiveness is
`already well-established in other settings and the study demonstrates a PK-PD relationship
`that is similar to, or different in an interpretable way from the established setting
`
`In general, the more critical a role that exposure-response information is to play in the
`establishment of efficacy, the more critical it is that it be derived from an adequate and well-
`controlled study (see 21 CFR 314.126), whatever endpoints are studied. Thus, we recommend
`that critical studies (1) have prospectively defined hypotheses/objectives, (2) use an appropriate
`control group, (3) use randomization to ensure comparability of treatment groups and to
`minimize bias, (4) use well-defined and reliable methods for assessing response variables, and
`(5) use other techniques to minimize bias.
`
`3
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`In contrast, some of the exposure-response studies considered in this document include analyses
`of nonrandomized data sets where associations between volunteer or patient exposure patterns
`and outcomes are examined. These analyses are often primarily exploratory, but along with
`other clinical trial data may provide additional insights into exposure-response relationships,
`particularly in situations where volunteers or patients cannot be randomized to different
`exposures, such as in comparing effects in demographic subgroups.
`
`1.
`
`Contributing to Primary Evidence of Effectiveness and/or Safety
`
`A dose-response study is one kind of adequate and well-controlled trial that can provide
`primary clinical evidence of effectiveness. The dose-response study is a particularly
`informative design, allowing observations of benefits and risks at different doses and
`therefore providing an ability to weigh the benefits and risks when choosing doses. The
`dose-response study can help ensure that excessive doses (beyond those that add to
`efficacy) are not used, offering some protection against unexpected and unrecognized
`dose-related toxicity. Captopril, for example, was a generally well-tolerated drug that
`caused dose and concentration-related agranulocytosis. Earlier recognition that daily
`doses beyond 75-150 milligrams were not necessary, and that renal impairment led to
`substantial accumulation, might have avoided most cases of agranulocytosis.
`
`Dose-response studies can, in some cases, be particularly convincing and can include
`elements of internal consistency that, depending on the size of the study and outcome,
`can allow reliance on a single clinical efficacy study as evidence of effectiveness. Any
`dose-response study includes several comparisons (e.g., each dose vs. placebo, each dose
`vs. lower doses). A consistent ordering of these responses (most persuasive when, for
`example, several doses are significantly different from placebo and, in addition, show an
`increasing response with dose) represents at least internal (within-study) replication,
`reducing the possibility that an apparent effect is due to chance. In principle, being able
`to detect a statistically significant difference in pairwise comparisons between doses is
`not necessary if a statistically significant trend (upward slope) across doses can be
`established, as described in the ICH E4 guidance on dose-response. It may be advisable,
`however, if the lowest dose tested is to be recommended, to have additional data on that
`dose.
`
`In some cases, measurement of systemic exposure levels (e.g., plasma drug
`concentrations) as part of dose-response studies can provide additional useful
`information. Systemic exposure data are especially useful when an assigned dose is
`poorly correlated with plasma concentrations, obscuring an existing concentration-
`response relationship. This can occur when there is a large degree of interindividual
`variability in pharmacokinetics or there is a nonlinear relationship between dose and
`plasma drug concentrations. Blood concentrations can also be helpful when (1) both
`parent drug and metabolites are active, (2) different exposure measures (e.g., Cmax,
`AUC) provide different relationships between exposure and efficacy or safety, (3) the
`number of fixed doses in the dose-response studies is limited, and (4) responses are
`highly variable and it is helpful to explore the underlying causes of variability of
`response.
`
`4
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`2.
`
`Providing Support for Primary Efficacy Studies
`
`Exposure-response information can support the primary evidence of safety and/or
`efficacy. In some circumstances, exposure-response information can provide important
`insights that can allow a better understanding of the clinical trial data (e.g., in explaining
`a marginal result on the basis of knowledge of systemic concentration-response
`relationships and achieved concentrations). Ideally, in such cases the explanation would
`be further tested, but in some cases this information could support approval. Even when
`the clinical efficacy data are convincing, there may be a safety concern that exposure-
`response data can resolve. For example, it might be reassuring to observe that even
`patients with increased plasma concentrations (e.g., metabolic outliers or patients on
`other drugs in a study) do not have increased toxicity in general or with respect to a
`particular concern (e.g., QT prolongation). Exposure-response data thus can add to the
`weight of evidence of an acceptable risk/benefit relationship and support approval. The
`exposure-response data might also be used to understand or support evidence of subgroup
`differences suggested in clinical trials, and to establish covariate relationships that
`explain, and enhance the plausibility of, observed subgroup differences in response.
`
`Exposure-response data using short-term biomarkers or surrogate endpoints can
`sometimes make further exposure-response data from clinical endpoint exposure-
`response studies unnecessary. For example, if it can be shown that the short-term effect
`does not increase past a particular dose or concentration, there may be no reason to
`explore higher doses or concentrations in the clinical trials. Similarly, short-term
`exposure-response studies with biomarkers might be used to evaluate early (e.g., first
`dose) responses seen in clinical trials.
`
`3.
`
`Supporting New Target Populations, Use in Subpopulations, Doses/Dosing
`Regimens, Dosage Forms, and Routes of Administration
`
`Exposure-response information can sometimes be used to support use, without further
`clinical data, of a drug in a new target population by showing similar (or altered in a
`defined way) concentration-response relationships for a well-understood (i.e., the shape
`of the exposure-response curve is known), short-term clinical or pharmacodynamic
`endpoint. Similarly, this information can sometimes support the safety and effectiveness
`of alterations in dose or dosing interval or changes in dosage form or formulation with
`defined PK effects by allowing assessment of the consequences of the changes in
`concentration caused by these alterations. In some cases, if there is a change in the mix
`of parent and active metabolites from one population (e.g., pediatric vs. adult), dosage
`form (e.g., because of changes in drug input rate), or route of administration, additional
`exposure-response data with short-term endpoints can support use in the new population,
`the new product, or new route without further clinical trials.
`
`a.
`
`New target populations
`
`5
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`A PK-PD relationship or data from an exposure-response study can be used to
`support use of a previously approved drug in a new target patient population, such
`as a pediatric population, where the clinical response is expected to be similar to
`the adult population, based on a good understanding of the pathophysiology of the
`disease, but there is uncertainty as to the appropriate dose and plasma
`concentration. A decision tree illustrating the use of a PK-PD relationship for
`bridging efficacy data in an adult population to a pediatric population is shown in
`Appendix B. Possible use of PK-PD bridging studies assessing a well-described
`PD endpoint (e.g., beta-blockade, angiotensin I or II inhibition) to allow extension
`of clinical trial information performed in one region to another region is discussed
`in the ICH E5 guidance on Ethnic Factors in the Acceptability of Foreign Clinical
`Data.
`
`b.
`
`Adjustment of dosages and dosing regimens in subpopulations defined on
`the basis of intrinsic and extrinsic factors
`
`Exposure-response information linking dose, concentration, and response can
`support dosage adjustments in patients where pharmacokinetic differences are
`expected or observed to occur because of one or more intrinsic (e.g.,
`demographic, underlying or accompanying disease, genetic polymorphism) or
`extrinsic (e.g., diet, smoking, drug interactions) factors. In some cases, this is
`straightforward, simply adjusting the dose to yield similar systemic exposure for
`that population. In others, it is not possible to adjust the dose to match both Cmax
`and AUC. Exposure-response information can help evaluate the implications of
`the different PK profiles. In some cases, exposure-response information can
`support an argument that PK changes in exposure would be too small to affect
`response and, therefore, that no dose or dose regimen adjustments are appropriate.
`
`c.
`
`New dose regimens, dosage forms and formulations, routes of
`administration, and minor product changes.
`
`A known exposure-response relationship can be used to (1) interpolate previous
`clinical results to new dosages and dosing regimens not well studied in clinical
`trials, (2) allow marketing of new dosage forms and formulations, (3) support
`different routes of administration, and (4) ensure acceptable product performance
`in the presence of changes in components, composition, and method of
`manufacture that lead to PK differences. Generally, these uses of exposure-
`response information are based on an understanding of the relationship between
`the response and concentration, and between dose and concentration.
`
`Exposure-response data can sometimes be used to support a new dose or dosing
`schedule (e.g., twice a day to once a day) that was not studied in safety and
`efficacy clinical trials. Exposure-response information can provide insight into
`the effect of the change in concentrations achieved with these changes and
`whether or not this will lead to a satisfactory therapeutic response. The new
`regimen would usually be within the range of total doses studied clinically, but in
`
`6
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`certain circumstances could be used to extend an approved dose range without
`additional clinical safety and efficacy data. For example, a once-daily dosing
`regimen could produce a higher Cmax and a lower Cmin than the same dose
`given as a twice-daily regimen. If exposure-response data were available, it might
`be considered reasonable to increase the recommended daily dose to maintain a
`similar Cmin, even without further studies. Exposure-response data are not likely
`to be useful in lieu of clinical data in supporting new dosing schedules unless the
`relationship of the measured responses to relevant safety and efficacy outcomes is
`well understood.
`
`In some cases, exposure-response data can support the approval of a new drug
`delivery system (e.g., a modified-release dosage form) when the PK profile is
`changed intentionally relative to an approved product, generally an immediate-
`release dosage form. A known exposure-response relationship could be used to
`determine the clinical significance of the observed differences in exposure, and to
`determine whether additional clinical efficacy and/or safety data are
`recommended.
`
`Exposure-response data can also support a new formulation that is unintentionally
`pharmacokinetically different from the formulation used in the clinical trials to
`demonstrate safety, or efficacy and safety. In the case of new drugs, in vitro
`and/or in vivo bioequivalence testing alone is usually used to show that the
`performance of a new formulation (e.g., to-be-marketed formulation) is equivalent
`to that used to generate the primary efficacy and safety data. It is possible to
`demonstrate differences in exposure that are real but not clinically important, even
`when the 90% confidence interval for the bioequivalence measures fall within the
`standard of 80-125%. It is possible for these bioequivalence studies to fail to
`meet the standard bioequivalence acceptance intervals of 80-125%. Rather than
`reformulating the product or repeating the bioequivalence study, a sponsor may be
`able to support the view that use of a wider confidence interval or accepting a real
`difference in bioavailability or exposure would not lead to a therapeutic
`difference. In other cases, where the altered bioavailability could be of clinical
`consequence, adjustment of the marketed dosage strength might be used to adjust
`for the PK difference.
`
`In the case of biological drugs, changes in the manufacturing process often lead to
`subtle unintentional changes in the product, resulting in altered pharmacokinetics.
`In cases in which the change in product can be determined not to have any
`pharmacologic effects (e.g., no effect on unwanted immunogenicity), exposure-
`response information may allow appropriate use of the new product. Exposure-
`response data are not likely to obviate the need for clinical data when formulation
`or manufacturing changes result in altered pharmacokinetics, unless the
`relationships between measured responses and relevant clinical outcomes are well
`understood.
`
`7
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`Exposure-response information could also be used to support a change in route of
`administration of a drug. An established exposure-response relationship would
`allow interpretation of the clinical significance of the difference in PK related to
`the different route. Such information about active metabolites could also be
`important in this situation.
`
`IV.
`
`DOSE-CONCENTRATION-RESPONSE RELATIONSHIPS
`AND EFFECTS OVER TIME
`
`Depending on the purpose of the study and the measurements made, exposure-response
`information can be obtained at steady state without consideration of the impact of fluctuations in
`exposure and response over time, or can be used to examine responses at the various
`concentrations attained after a single dose during the dosing interval or over the course of
`treatment. Where effectiveness is immediate and is readily measured repeatedly in the course of
`a dosing interval (e.g., analgesia, blood pressure, blood glucose), it is possible to relate clinical
`response to blood concentrations over time, which can provide critical information for choosing
`a dose and dosing interval. This is standard practice with antihypertensives, for example, where
`effect at the end of the dose interval and at the time of the peak plasma concentration is routinely
`assessed and where 24-hour automated BP measurements are often used. Controlled-release
`decongestants have also been assessed for their effects over the dosing interval, especially the
`last several hours of the dosing interval.
`
`Often, however, the clinical measurement is delayed or persistent compared to plasma
`concentrations, resulting in an exposure-response relationship with considerable hysteresis.
`Even in this case, exposure-response relationships can be informative. Furthermore, safety
`endpoints can have a time-dependent concentration-response relationship and it could be
`different from that of the desired effect.
`
`A.
`
`Dose and Concentration-Time Relationships
`
`As noted in the ICH E4 guidance for industry on Dose-Response Information to Support Drug
`Registration, dose-response information can help identify an appropriate starting dose and
`determine the best way (how often and by how much) to adjust dosage for a particular patient. If
`the time course of response and the exposure-response relationship over time is also assessed,
`time-related effects on drug action (e.g., induction, tolerance, and chronopharmacologic effects)
`can be detected. In addition, testing for concentration-response relationships within a single
`dosing interval for favorable and adverse events can guide the choice of dosing interval and dose
`and suggest benefits of controlled-release dosage forms. The information on the effects of dose,
`concentration, and response can be used to optimize trial design and product labeling.
`
`Although dose is the measurement of drug exposure most often used in clinical trials, it is plasma
`concentration measurements that are more directly related to the concentration of the drug at the
`target site and thus to the effect. Relationships between concentration and response can, of
`course, vary among individuals, but concentration-response relationships in the same individual
`over time are especially informative because they are not potentially confounded by dose-
`selection/titration phenomena and inter-individual PK variability.
`
`8
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`B.
`
`Concentration-Response Relationships: Two Approaches
`
`There are two fundamentally different approaches to examining plasma concentration-response
`relationships: (1) observing the plasma concentrations attained in patients who have been given
`various doses of drug and relating the plasma concentrations to observed response; and (2)
`assigning patients randomly to desired plasma concentrations, titrating dose to achieve them, and
`relating the concentration to observed response. In some cases, concentration-response
`relationships obtained from these studies can provide insight over and above that obtained
`through looking at the dose-response relationship.
`
`The first kind of study (# 1 above) is the usual or most common way of obtaining exposure-
`response information, but this kind of study can be misleading unless it is analyzed using
`specialized approaches (e.g., Sheiner, Hashimoto, and Beal 1991). Even when appropriately
`analyzed, potential confounding of the concentration-response relationship can occur and an
`observed concentration-response relationship may not be credible evidence of an exposure-
`response relationship. (See ICH E4). For example, if it were found that patients with better
`absorption, and thus higher concentrations, had greater response, this might not be related to the
`higher concentrations but to another factor causing both the greater absorption and the greater
`response. Similarly, renal failure could simultaneously lead to increased plasma concentrations
`and susceptibility to adverse effects, leading to an erroneous conclusion that concentration is
`related to adverse effects. Also, a study that titrated only nonresponders to higher doses might
`show a lower response with higher concentrations (i.e., a bell-shaped concentration-response (or
`dose-response) curve, a result that would not reflect the true population exposure-response
`relationship). Thus, although it is useful to look in data for such relationships, we suggest that
`they be subjected to further evaluation. The potential problem of interrelated factors leading to
`both an effect on pharmacokinetics and an effect on response and therefore an erroneous
`concentration-response relationship when individuals are not randomized to concentrations
`generally does not occur when concentration-response relationships in the same individual are
`observed over time (e.g., over a dosing interval).
`
`The second kind of study (# 2 above) is the randomized, concentration-controlled trial (e.g.,
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