Novel anti-tumor therapy with liposomal glucocorticoids: MRI monitoring of drug delivery Ewelina Kluza1, Sin Yuin Yeo1, Daisy W. J. van der Schaft1,2, Willem Mulder3, Raymond M. Schiffelers4, Gert Storm4, Gustav J. Strijkers1 and 1Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; 2 Soft Tissue Biomechanics and Engineering, D
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E4step4.docINTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICALREQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMANUSE ICH HARMONISED TRIPARTITE GUIDELINE
DOSE-RESPONSE INFORMATION TO SUPPORT DRUG
This Guideline has been developed by the appropriate ICH Expert Working Groupand has been subject to consultation by the regulatory parties, in accordance with theICH Process. At Step 4 of the Process the final draft is recommended for adoption tothe regulatory bodies of the European Union, Japan and USA.
DOSE-RESPONSE INFORMATION TO SUPPORT DRUG REGISTRATION
ICH Harmonised Tripartite Guideline
Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 10 March 1994, this guideline is recommended for adoption INTRODUCTION
Purpose of Dose-Response Information
Knowledge of the relationships among dose, drug-concentration in blood, and clinicalresponse (effectiveness and undesirable effects) is important for the safe and effectiveuse of drugs in individual patients. This information can help identify an appropriatestarting dose, the best way to adjust dosage to the needs of a particular patient, and adose beyond which increases would be unlikely to provide added benefit or wouldproduce unacceptable side effects. Dose-concentration, concentration- and/or dose-response information is used to prepare dosage and administration instructions inproduct labeling. In addition, knowledge of dose-response may provide an economicalapproach to global drug development, by enabling multiple regulatory agencies tomake approval decisions from a common database.
Historically, drugs have often been initially marketed at what were later recognizedas excessive doses (i.e., doses well onto the plateau of the dose-response curve for thedesired effect), sometimes with adverse consequences (e.g. hypokalemia and othermetabolic disturbances with thiazide-type diuretics in hypertension). This situationhas been improved by attempts to find the smallest dose with a discernible usefuleffect or a maximum dose beyond which no further beneficial effects is seen, butpractical study designs do not exist to allow for precise determination of these doses.
Further, expanding knowledge indicates that the concepts of minimum effective doseand maximum useful dose do not adequately account for individual differences and donot 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 singledose 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 andlocation of the population (group) average dose-response curve for both desirable andundesirable effects. Selection of dose is best based on that information, together witha judgement about the relative importance of desirable and undesirable effects. Forexample, a relatively high starting dose (on or near the plateau of the effectivenessdose-response curve) might be recommended for a drug with a large demonstratedseparation between its useful and undesirable dose ranges or where a rapidlyevolving disease process demands rapid effective intervention. A high starting dose,however, might be a poor choice for a drug with a small demonstrated separationbetween its useful and undesirable dose ranges. In these cases, the recommendedstarting dose might best be a low dose exhibiting a clinically important effect in evena fraction of the patient population, with the intent to titrate the dose upwards aslong as the drug is well-tolerated. Choice of a starting dose might also be affected bypotential intersubject variability in pharmacodynamic response to a given bloodconcentration level, or by anticipated intersubject pharmacokinetic differences, such Dose-Response Information to Support Drug Registration as could arise from non-linear kinetics, metabolic polymorphism, or a high potentialfor pharmacokinetic drug-drug interactions. In these cases, a lower starting dosewould protect patients who obtain higher blood concentrations. It is entirely possiblethat different physicians and even different regulatory authorities would, looking atthe same data, make different choices as to the appropriate starting doses, dosetitration steps, and maximum recommended dose, based on different perceptions ofrisk/benefit relationships. Valid dose-response data allow the use of such judgement.
In adjusting the dose in an individual patient after observing the response to aninitial 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) averagedose-response curve. Study designs that allow estimation of individual dose-responsecurves could therefore be useful in guiding titration, although experience with suchdesigns and their analysis is very limited.
In utilizing dose-response information, it is important to identify, to the extentpossible, factors that lead to differences in pharmacokinetics of drugs amongindividuals, 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 concentrationmonitoring, the value of concentration-response information is obvious. In othercases, an established concentration-response relationship is often not needed, butmay be useful for ascertaining the magnitude of the clinical consequences of 1)pharmacokinetic differences, such as those due to drug-disease (e.g. renal failure) ordrug-drug interactions, or 2) for assessing the effects of the altered pharmacokineticsof new dosage forms (e.g. controlled release formulation) or new dosage regimenswithout need for additional clinical data, where such assessment is permitted byregional regulations. Prospective randomized concentration-response studies arecritical to defining concentration monitoring therapeutic “windows” but are alsouseful when pharmacokinetic variability among patients is great; in that case, aconcentration response relationship may in principle be discerned in a prospectivestudy with a smaller number of subjects than could the dose response relationship ina standard dose-response study. Note that collection of concentration-responseinformation does not imply that therapeutic blood level monitoring will be needed toadminister the drug properly. Concentration-response relationships can betranslated into dose-response information. Alternatively, if the relationships betweenconcentration and observed effects (e.g., an undesirable or desirable pharmacologiceffect) are defined, patient response can be titrated without the need for further bloodlevel monitoring. Concentration-response information can also allow selection ofdoses (based on the range of concentrations they will achieve) most likely to lead to asatisfactory response.
Problems with Titration Designs
A study design widely used to demonstrate effectiveness utilizes dose titration tosome effectiveness or safety endpoint. Such titration designs, without carefulanalysis, are usually not informative about dose-response relationships. In manystudies there is a tendency to spontaneous improvement over time that is not easilydistinguishable from an increased response to higher doses or cumulative drugexposure. This leads to a tendency to choose, as a recommended dose, the highest Dose-Response Information to Support Drug Registration dose used in such studies that was reasonably well-tolerated. Historically, thisapproach 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 forhypertension. In some cases, notably where an early answer is essential, thetitration-to-highest-tolerable-dose approach is acceptable, because it often requires aminimum number of patients. For example, the first marketing of zidovudine (AZT)for treatment of people with AIDS was based on studies at a high dose; later studiesshowed that lower doses were as effective and far better tolerated. The urgent needfor the first effective anti-HIV treatment made the absence of dose-responseinformation at the time of approval reasonable (with the condition that more datawere to be obtained after marketing), but in less urgent cases this approach isdiscouraged.
Interactions between Dose-Response and Time
The choice of the size of an individual dose is often intertwined with the frequency ofdosing. In general, when the dose interval is long compared to the half-life of thedrug, attention should be directed to the pharmacodynamic basis for the chosendosing interval. For example, there might be a comparison of the long dose-intervalregimen with the same dose in a more divided regimen, looking, where this isfeasible, for persistence of desired effect throughout the dose-interval and for adverseeffects associated with blood level peaks. Within a single dose-interval, the dose-response relationships at peak and through blood levels may differ and therelationship could depend on the dose interval chosen.
Dose-response studies should take time into account in a variety of other ways. Thestudy 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. Thedose-response may also be different for morning vs evening dosing. Similarly, thedose-response relationship during early dosing may not be the same as in thesubsequent maintenance dosing period. Responses could also be related tocumulative dose, rather than daily dose, to duration of exposure (e.g., tachyphylaxis,tolerance, or hysteresis) or 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 developmentwith studies designed to assess dose-response an inherent part of establishing thesafety and effectiveness of the drug. If development of dose-response information isbuilt into the development process it can usually be accomplished with no loss of timeand minimal extra effort compared to development plans that ignore dose-response.
Studies in Life-Threatening Diseases
In particular therapeutic areas, different therapeutic and investigational behaviorshave 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-threateninginfections or potentially curable tumors, at least if there were effective treatmentsknown. Moreover, because in those therapeutic areas considerable toxicity could beaccepted, relatively high doses of drugs are usually chosen to achieve the greatest Dose-Response Information to Support Drug Registration possible beneficial effect rapidly. This approach may lead to recommended doses thatdeprive some patients of the potential benefit of a drug by inducing toxicity that leadsto cessation of therapy. On the other hand, use of low, possibly subeffective, doses, orof titration to desired effect may be unacceptable, as an initial failure in these casesmay represent and opportunity for cure forever lost.
Nonetheless, even for life-threatening diseases, drug developers should always beweighing the gains and disadvantages of varying regimens and considering how bestto choose dose, dose-interval and dose-escalation steps. Even in indications involvinglife-threatening diseases, the highest tolerated dose, or the dose with the largesteffect on a surrogate marker will not always be the optimal dose. Where only singledose is studied, blood concentration data, which will almost always show considerableindividual variability due to pharmacokinetic differences, may retrospectively giveclues 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 planningan intervention study, the potential advantages of studying more than a single doseshould be considered. In some cases it may be possible to simplify the study bycollecting less information on each patient, allowing study of a larger populationtreated 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, sothat all appear equivalent (albeit superior to placebo). In that case, there is thepossibility that the lowest dose studied is still greater than needed to exert the drug’smaximum effect. Nonetheless, an acceptable balance of observed undesired effectsand 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 itdid not, in light of the studies that partly defined the proper dose range, further dose-finding might be pursued in the post-marketing period. Similarly, although seekingdose-response data should be a goal of every development program, approval based ondata from studies using a fixed single dose or a defined dose range (but without validdose-response information) might be appropriate where benefit from a new therapy intreating 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 toprovide it, the entire database should be examined intensively for possible dose-response effects. The limitations imposed by certain study design feature should ofcourse be appreciated. For example, many studies titrate the dose upward for safetyreasons. As most side effects of drugs occur early and may disappear with continuedtreatment, this can result in a spuriously higher rate of undesirable effects at thelower doses. Similarly, in studies where patients are titrated to a desired response,those patients relatively unresponsive to the drug are more likely to receive thehigher dose, giving an apparent, but misleading, inverted “U-shaped” dose-responsecurve. Despite such limitations, clinical data from all sources should be analyzed fordose-related covariate effects using multivariate, or other alternative, approaches,even if the analyses can yield principally hypotheses, not definitive conclusions. Forexample, an inverse relation of effect to weight or creatinine clearance could reflect adose-related covered relationship. If pharmacokinetics screening (obtaining a small Dose-Response Information to Support Drug Registration number of steady-state blood concentration measurements in most phase 2/3 studypatients) is carried out, or if other approaches to obtaining drug concentrationsduring trials are used, a relation of effects (desirable or undesirable) to bloodconcentrations may be discerned. The relationship may by itself be a persuasivedescription of concentration response or may suggest further study.
III. STUDY DESIGNS FOR ASSESSING DOSE-RESPONSE
The choice of study design and study population in dose-response trials will dependon the phase of development, therapeutic indication under investigation, and theseverity of the disease in the patient population of interest. For example, the lack ofappropriate salvage therapy for life threatening or serious conditions withirreversible outcomes may ethically preclude conduct of studies at doses below themaximal tolerated dose. A homogeneous patient population will generally allowachievement of study objectives with small numbers of subjects given each treatment.
On the other hand, larger, more diverse populations allow detection of potentiallyimportant covariate effects.
In general, useful dose-response information is best obtained from trials specificallydesigned to compare several doses. A comparison of results from two or morecontrolled trials with single fixed doses might sometimes be informative, e.g., ifcontrol groups were similar, although, even in that case, the many across-studydifferences 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 patientfactors, the information can be useful and can guide subsequent studies. Conductingdose-response studies at an early stage of clinical development may reduce thenumber of failed phase 3 trials, speeding the drug development process andconserving development resources.
Pharmacokinetic information can be used to choose doses that ensure adequatespread of attained concentration-response values and diminish or eliminate overlapbetween attained concentrations in dose-response trials. For drugs with highpharmacokinetic 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 whenthe response is measured by a continuous or categorical variable, is relatively rapidlyobtained 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 studydesigns can be used and relatively small , simple studies can give useful information.
Placebo-controlled individual subject titration designs typical of many early drugdevelopment studies, for example, properly conducted and analyzed (quantitativeanalysis that models and estimates the population and individual dose-responserelationships), 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, orirreversible (e.g., stroke or heart attack prevention, asthma prophylaxis, arthritis Dose-Response Information to Support Drug Registration treatments with late onset response, survival in cancer, treatment of depression),titration and simultaneous assessment of response is usually not possible, and theparallel dose-response study is usually needed. The parallel group, dose-responsestudy also offers protection against missing an effective dose because of an inverted“U-shaped” (umbrella or bell shaped) dose-response curve, where higher doses areless effective than lower doses, a response that can occur, for example, with mixedagonist-antagonists.
Trials intended to evaluate dose or concentration response should be well-controlled,using randomization and blinding (unless blinding is unnecessary or impossible) toassure 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 practicalityand patient safety to discern clinically meaningful differences. This is especiallyimportant where there are no pharmacologic or plausible surrogate endpoints to giveinitial guidance as to dose.
Specific Trial Designs
A number of specific study designs can be used to assess dose-response. The sameapproaches can also be used to measure concentration-response relationships.
Although not intended to be an exhaustive list, the following approaches have beenshown to be useful ways of deriving valid dose-response information. Some designsoutlined in this guidance are better established than others, but all are worthy ofconsideration. These designs can be applied to the study of established clinicalendpoints or surrogate endpoints.
Randomization to several fixed dose groups (the randomized parallel dose-response study) is simple in concept and is a design that has had extensive useand considerable success. The fixed dose is the final or maintenance dose;patients may be placed immediately on that dose or titrated gradually (in ascheduled “forced” titration) to it if that seems safer. In either case, the finaldose should be maintained for a time adequate to allow the dose-responsecomparison. Although including a placebo group in dose-response studies isdesirable, it is not theoretically necessary in all cases; a positive slope, evenwithout a placebo group, provides evidence of a drug effect. To measure theabsolute size of the drug effect, however, a placebo or comparator with verylimited effect on the endpoint of interest is usually needed. Moreover, because adifference between drug groups and placebo unequivocally shows effectiveness,inclusion of a placebo group can salvage, in part, a study that used doses thatwere all too high and therefore showed no dose-response slope, by showing thatall doses were superior to placebo. In principle, being able to detect astatistically significant difference in pairwise comparisons between doses is notnecessary if a statistically significant trend (upward slope) across doses can beestablished using all the data. It should be demonstrated, however, that thelowest dose(s) tested, if these are to be recommended, have a statisticallysignificant and clinically meaningful effect.
The parallel dose-response study gives group mean (population-average) dose-responses, not the distribution or shape of individual dose-response curves.
Dose-Response Information to Support Drug Registration It is all too common to discover, at the end of a parallel dose-response study, thatall doses were too high (on the plateau of the dose-response curve), or that dosesdid 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 doserange.
As with any placebo-controlled trial, it may also be useful to include one or moredoses of an active drug control. Inclusion of both placebo and active controlgroups allows assessment of “assay sensitivity”, permitting a distinction betweenan 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 alsorepresent a more valid and informative comparative effectiveness/safety studythan comparison of single doses of the two agents.
The factorial trial is a special case of the parallel dose-response study to beconsidered when combination therapy is being evaluated. It is particularly usefulwhen both agents are intended to affect the same response variable (a diureticand another anti-hypertensive, for example), or when one drug is intended tomitigate the side effects of the other. These studies can show effectiveness (acontribution of each component of the combination) and, in addition, providedosing information for the drugs used alone and together.
A factorial trial is a parallel group, fixed-dose design that uses a range of doses ofeach separate drug and some or all combinations of these doses. The sample sizeneed not be large enough to distinguish single cells from each other in pair-wisecomparisons because all of the data can be used to derive dose-responserelationships for the single agents and combinations, i.e., a dose-responsesurface. These trials therefore can be of moderate size. The doses andcombinations that could be approved for marketing might not be limited to theactual doses studied but might include dose and combinations in between thosestudied. There may be some exceptions to the ability to rely entirely on theresponse surface analysis in choosing dose(s). At the low end of the dose range, ifthe 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 bedistinguished from placebo in a pair-wise comparison. One way to do this in thefactorial study is to have the lowest dose combination and placebo groups besomewhat larger than other groups; another is to have a separate study of thelow-dose combination. Also, at the high end of the dose range, it may benecessary to confirm the contribution of each component to the overall effect.
A randomized multiple cross-over study of different doses can be successful ifdrug effect develops rapidly and patients return to baseline conditions quicklyafter cessation of therapy, if responses are not irreversible (cure, death), and ifpatients have reasonably stable disease. This design suffers, however, from thepotential problems of all cross-over studies: it can have analytic problems if thereare many treatment withdrawals; it can be quite long in duration for anindividual patient; and there is often uncertainty about carry-over effects (longertreatment periods may minimize this problem), baseline comparability after thefirst period, and period-by-treatment interactions. The length of the trial can bereduced by approaches that do not require all patients to receive each dose, suchas balanced incomplete block designs.
Dose-Response Information to Support Drug Registration The advantages of the design are that each individual receives several differentdoses so that the distribution of individual dose-response curves may beestimated, as well as the population average curve, and that, compared to aparallel group design, fewer patients may be needed. Also, in contrast totitration designs, dose and time are not confounded and carry-over effects arebetter assessed.
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. Ifmost patients complete all doses, and if the study is controlled with a parallelplacebo-group, the forced titration study allows a series of comparisons of anentire 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 toincreased time on drug therapy or a cumulative drug dosage effect. It istherefore an unsatisfactory design when response is delayed, unless treatment ateach dose is prolonged. Even where the time-until-development of effect is knownto be short (from other data), this design gives poor information on adverseeffects, many of which have time-dependent characteristics. A tendency towardspontaneous improvement, a very common circumstance, will be revealed by theplacebo group, but is also a problem for this design, as over time the higher dosesmay find little room to show an increased effect. This design can give areasonable first approximation of both population-average dose-response and thedistribution of individual dose-response relationships if the cumulative (time-dependent) drug effect is minimal and the number of treatment withdrawals isnot excessive. Compared to a parallel dose-response study, this design may usefewer patients, and can, by extending the study duration, be used to investigate awide range of doses, again making it a reasonable first study. With a concurrentplacebo group this design can provide clear evidence of effectiveness, and may beespecially valuable in helping choose doses for a parallel dose-response study.
Optional titration (placebo-controlled titration to end-point)
In this design patients are titrated until they reach a well characterizedfavorable or unfavorable response, defined by dosing rules expressed in theprotocol. This approach is most applicable to conditions where the response isreasonably prompt and is not an irreversible event, such as stroke or death. Acrude analysis of such studies, e.g., comparing the effects in the subgroups ofpatients titrated to various dosages, often gives a misleading inverted “U-shaped”curve, as only poor responders are titrated to the highest dose. However, moresophisticated statistical analytical approaches that correct for this, by modelingand estimating the population and individual dose-response relationships,appear to allow calculation of valid dose-response information. Experience inderiving valid dose-response information in this fashion is still limited. It isimportant, in this design, to maintain a concurrent placebo group to correct forspontaneous changes, investigator expectations, etc. Like other designs that useseveral doses in the same patient, this design may use fewer patients than aparallel fixed dose study of similar statistical power and can provide bothpopulation average and individual dose-response information. The design does,however, risk confounding of time and dose effects and would be expected to have Dose-Response Information to Support Drug Registration 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. Ittoo may be especially valuable as an early study to identify doses for a definitiveparallel study.
Dose-Response Information to Support Drug Registration IV. GUIDANCE AND ADVICE
Dose-response data are desirable for almost all new chemical entities enteringthe market. These data should be derived from study designs that are sound andscientifically based; a variety of different designs can give valid information. Thestudies should be well-controlled, using accepted approaches to minimize bias. Inaddition to carrying out formal dose-response studies, sponsors should examinethe entire database for possible dose-response information.
The information obtained through targeted studies and analyses of the entiredatabase should be used by the sponsor to: Identify a reasonable starting dose, ideally with specific adjustments (or afirm basis for believing none is needed) for patient size, gender, age,concomitant illness, and concomitant therapy, reflecting an integration ofwhat is known about pharmacokinetic and pharmacodynamic variability.
Depending on circumstances (the disease, the drug’s toxicity) the startingdose may range from a low dose with some useful effect to a dose that is at ornear the full-effect dose.
Identify reasonable, response-guided titration steps, and the interval atwhich they should be taken, again with appropriate adjustments for patientcharacteristics. These steps would be based either on the shape of the typicalindividual’s dose-effect curves (for both desirable and undesirable effects), ifindividual dose-response data were available, or if not, on the shape of thepopulation (group)-average dose-response, and the time needed to detect achange in these effects. It should be noted that methodology for finding thepopulation (group)-average dose-response is, at present, better establishedthan is methodology for finding individual dose-response relationships.
Identify a dose, or a response (desirable or undesirable), beyond whichtitration should not ordinarily be attempted because of a lack of furtherbenefit or an unacceptable increase in undesirable effects.
It is prudent to carry out dose-ranging or concentration-response studies early indevelopment as well as in later stages in order to avoid failed phase 3 studies oraccumulation of a database that consists largely of exposures at ineffective orexcessive doses. The endpoints of studies may vary at different stages of drugdevelopment. For example, in studying a drug for heart failure, apharmacodynamic endpoint might be used early (e.g., cardiac output, wedgepressure), an intermediate endpoint might be used later (e.g., exercise tolerance,symptoms) and a mortality or irreversible morbidity endpoint might be the finalassessment (survival, new infarction). It should be anticipated that the dose-response for these endpoints may be different. Of course, the choice of endpointsthat must be studied for marketing approval will depend on the specific situation.
A widely used, successful and acceptable design, but not the only study design forobtaining population average dose-response data, is the parallel, randomizeddose-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 ofdrug dosage, or drug concentration, to clinical beneficial or undesirable effectscan be defined.
Dose-Response Information to Support Drug Registration 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 doselevel of drug versus placebo allows a test of the null hypothesis of no differencebetween drug and placebo, but cannot define the dose-response relationship.
Similarly, although a linear relationship can be derived from the response to twoactive doses (without placebo), this approximation is usually not sufficientlyinformative. Study designs usually should emphasize elucidation of the dose-response function, not individual pairwise comparisons. If a particular point onthe curve, e.g., whether a certain low dose is useful, becomes an issue, it shouldbe studied separately.
Dose-response data for both beneficial and undesirable effects may provideinformation that allows approval of a range of doses that encompass anappropriate benefit to risk ratio. A well-controlled dose-response study is also astudy that can serve as primary evidence of effectiveness.
Regulatory agencies and drug developers should be open to new approaches andto the concept of reasoned and well documented exploratory data analysis ofexisting or future databases in search of dose-response data. Agencies shouldalso be open to the use of various statistical and pharmacometric techniques suchas Bayesian and population methods, modeling, and pharmacokinetic-pharmacodynamic approaches. However, these approaches should not subvertthe requirement for dose-response data from prospective, randomized, multi-dose-level clinical trials. Post-hoc explanatory data analysis in search of dose-response information from databases generated to meet other objectives willoften generate new hypotheses, but will only occasionally provide definitiveassessment of dose-response relationships.
A variety of data analytical techniques, including increased use of retrospectivepopulation-type analyses, and novel designs (e.g., sequential designs) may helpdefine the dose-response relationship. For example, fixed dose designs can bereanalyzed as a continuum of dose levels if doses are refigured on a mg/kg basis,or adjusted for renal function, lean body mass, etc. Similarly, blood levels takenduring a dose-response study may allow estimates of concentration-responserelationships. Adjustment of drug exposure levels might be made on the basis ofreliable information on drug taking compliance. In all of these cases, one shouldalways be conscious of confounding, i.e., the presence of a factor that alters boththe refigured dose and response or that alters both blood level and response,compliance and response, etc.
Dose-response data should be explored for possible differences in subsets basedon demographic characteristics, such as age, gender or race. To do this it isimportant to know whether there are pharmacokinetic differences among thesegroups, e.g. due to metabolic differences, differences in body habitus orcomposition, etc.
Approval decisions are based on a consideration of the totality of information on adrug. Although dose-response information should be available, depending on thekind and degree of effectiveness shown, imperfections in the database may beacceptable with the expectation that further studies will be carried out afterapproval. Thus, informative dose-response data, like information on responses inspecial populations, on long-term use, on potential drug-drug and drug-diseaseinteractions, is expected, but might, in the face of a major therapeutic benefit or Dose-Response Information to Support Drug Registration urgent need, or very low levels of observed toxicity, become a deferredrequirement.
La Maladie d’Alzheimer : Perspectives Thérapeutiques MOTS-CLES : MALADIE D’ALZHEIMER, TRAITEMENT, INHIBITEUR DE L’ACETYLCHOLINESTERASE, IMMUNOTHERAPIE Alzheimer’s disease: Therapeutic perspectives KEY-WORDS: ALZHEIMER’S DISEASE, TREATMENT, CHOLINESTERASE INHIBITORS, IMMUNOTHERAPY Bruno DUBOIS*, Leonardo De SOUZA, Gilles ALLALI, Michel KALAFAT, Marie SARAZIN RESUME :