WO2010090730A1

WO2010090730A1 - Method, apparatus and software for identifying responders in a clinical environment

Info

Publication number: WO2010090730A1
Application number: PCT/US2010/000298
Authority: WO
Inventors: Ron Cohen; Andrew R. Blight; Lawrence Marinucci
Original assignee: Acorda Therapeutics, Inc.
Priority date: 2009-02-03
Filing date: 2010-02-03
Publication date: 2010-08-12

Abstract

A process for determining responders in clinical testing environments that involves, inter alia, detecting treatment response through the use of small numbers of measurements of randomly varying outcome variables in individual clinical trial subjects, and by analyzing the measurements in such a way as to eliminate troublesome variables, such as a spontaneous population variability.

Description

METHOD, APPARATUS AND SOFTWARE FOR IDENTIFYING RESPONDERS IN A

CLINICAL ENVIRONMENT

BACKGROUND

[0001] Clinical researchers have the ongoing problem of not being able to accurately predict or plan future trials, and are not able to salvage or otherwise learn from failed clinical trials. There are many reasons for this. First, functional measurements from clinical trial subjects with certain kinds of conditions like MS and other ailments can vary extensively and randomly over time. This is problematic, because if these measurements are to be used as treatment outcome measures, the spontaneous variability can obscure the treatment-related effects. This interference between spontaneous and induced changes may be particularly problematic under conditions where only a subset of trial subjects respond to treatment. Under these conditions, the treatment effect in the responsive subjects may be diluted by the non- responders in addition to the contamination of spontaneous variability.

[0002] Moreover, clinical trials also frequently rely on just a few, intermittent measurements at widely spaced clinic visits. These few sample measurements will not adequately represent the full range of variation of the outcome variable, either during the baseline comparison period or during the treatment period. Where the magnitude of the spontaneous variability of the population is large compared to the expected treatment effect in the individual, it can be difficult to determine the presence of response to treatment based on the average difference between baseline and treatment periods. A single large outlying value in one direction or the other from the mean may mask a smaller but consistent response or alternatively produce the impression of a response that is not actually consistent during the treatment period. Thus, there is a need for detecting a consistent response to treatment over time without encountering false results from the above-mentioned variables.

[0003] It is therefore an object of the invention to provide a means to detect true, consistent response to treatment over time using small numbers of measurements from on- treatment and off-treatment periods has been devised to provide a solution for this problem.

[0004] It is further an object of the present invention to provide a method that involves examining the frequency with which values measured during the on-treatment period lie outside the range of values recorded during the off-treatment period(s) of the trial. SUMMARY OF TH E INVENTION

[0005] This invention relates to a method, apparatus, and computer software application that can be used to analyze therapeutic effect of a treatment of patients in a clinical environment.

[0006] More specifically, the present invention may be utilized to analyze the response of patients in a clinical environment for many different types of afflictions, including, but not limited to, neurological disorders such as multiple sclerosis, spinal cord injuries, Alzheimer's disease and ALS.

[0007] One embodiment of the present invention relates to a method, apparatus and software program for analyzing clinical patient treatment data in order to predict future clinical trials.

[0008] Another embodiment of the present invention relates to a method, apparatus and software program for analyzing clinical patient treatment data in order to derive value from completed clinical trials, regardless of the outcome of the particular trial.

[0009] Another embodiment of the present invention relates to a method, apparatus and software program for selecting individuals based on responsiveness to a treatment. The method comprises identifying a plurality of individuals; administering a test to each individual prior to a treatment period; administering a treatment to one or more of the individuals during the treatment period; administering the test a plurality of times to each individual during the treatment period; and selecting one or more individuals, wherein the selected individuals exhibit an improved performance during a majority of the tests administered during the treatment period as compared to the test administered prior to the treatment period. In certain embodiments, the method may further comprise administering the test to each individual after the treatment period, wherein the selected individuals further exhibit an improved performance during a majority of the tests administered during the treatment period as compared to the test administered after the treatment period.

[0010] A further embodiment relates to a method of selecting individuals based on responsiveness to a treatment, the method comprising identifying a plurality of individuals; administering a test to each individual prior to a treatment period; administering a treatment to one or more of the individuals during the treatment period; administering the test a plurality of times to each individual during the treatment period; administering the test to each individual after the treatment period; and selecting one or more individuals, wherein the selected individuals exhibit an improved performance during a majority of the tests administered during the treatment pcriod as coinpai cd to the better per foi maiicc of the test administer ccl pi 101 to the ti calmenl pci iod and tlic test aclministerecl after the treatment period

BRIEF DESCRI PTION OF THE DRAWINGS

[0011] Figure 1 is an exemplary flow diagram showing one way in which the inventive process may be put forth in a computer aided embodiment so treatment data from a clinical trial of a given nυmber of patients may analyzed to determine the iesponders therein,

[0012] Figure 2 is an exemplaiy flow diagram showing one way in which the probability distribution generation of the inventive process may be put forth in a computer aided embodiment tn Older to offer a comparative baseline against responder values,

[0013] Figure 3 is a generalized system level block diagram of an exemplary system employing the inventive process described herein, and

[0014] Figures 4 (a) — 4 (d) are histograms and distribution graphs of responder and non- responder populations shown in the context of the an illustrative utilization of the present invention

DETAILED DESCRIPTION OF THE INVENTION

[0015] Before the piesent compositions and methods are described, it is to be understood that this invention is not limited to the particular molecules, compositions, methodologies or protocols descnbed, as these may vary It is also to be understood that the terminology used in the description is for the purpose of desciibing the particular versions oi embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims

[0016] The terms used herein have meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below

[0017] It must also be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context cleai ly dictates otherwise Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art Although any methods and materials similar or equivalent to those descnbed herein can be used in the practice oi testing of embodiments of the present invention the preferred methods devices, and materials ate now described All publications mentioned hci ein aie incoi poiated by reference. Nothing hciein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue ot puor invention

[0018] "Software" means all forms of electronically executable code, iegardless of the language employed for coding, specific system architecture coded for, and regardless of storage medium utilized (disk, download ASP, etc )

[0019] The terms "patient ' and "sub|ect" mean all animals including humans Examples of patients or subjects include humans, cows, dogs, cats, goats, sheep, rats, pigs, etc

[0020] One aspect of the invention therefore relates to a process of providing foi the above mentioned fiequency to be compared between treatment and control groups, as well as with the predictions ot a simple computer model based on random number generation Hence, if there aiey measurements made during treatment and /c measurements made during the non- treatment period, a computer model can be generated that will predict the frequency with which a given subset of the / measurements will exceed the largest of the k off treatment measurements This is effectuated by using the method and the computer program of the present invention to generate many thousands of stiings of j+k random numbers within a preset range and testing the frequency with which numbers in they set exceed all numbers in the k set Over the course of many thousand iterations, it will be possible to determine the probability that 1 ,2,3 j of the_/ set will exceed all the k set within any one iteration

[0021] By way of just one illustration, wheny and k arc small integers (say, >3,<8) there will be a relatively high piobabihty that just (or at least) one of they set exceeds the maximum of the k set, but the probability will deciease iapidly for higher numbers ot they set, with the least probability that all of the numbers in the _/ set will be higher than the maximum of the k set As such, the model will then be able to generate a probability distribution for the number of_/ on- treatment measurements that are likely to exceed the maximum of the k off-treatment measurements The clinical trial data ior each individual subject oi patient P can be examined directly for the number of on-treatment measuiementb that exceed the maximum off-tieatmeπt measurement The distiibution of the number of/ measurements that exceed the maximum k measurement for individuals in the treated group may then be compaied with the similar distribution for the placebo-treated or other comparatoi group

[0022] Differences in the distribution should then be present for the higher numbers ofy measurements that exceed the maximum k measurement These differences allow a suitable criterion to be established for the minimum number ofy values exceeding the maximum k value that represents a high likelihood of a tieatment response, based on a clear separation of probability in the upper part of the i angc A working criterion would be that a treatment response is likely where a majority of the j mcasuicmenrs exceed the maximum k measurement, under the condition that j and k are closely matched small integers (plus or minus one). The probability that the majority of j values lie above the range of k values should be low based on random variability

[0023] Similarly, the clinical trial data may also be compared to the piobabihty distribution from the computer model to check that the probability distribution of the comparator data is similar to the random number model and that there is not a profound deviation from the predictions of the model that would indicate a tieatment-penod telated effect that was independent of tieatment

[0023] Once the criterion for response can be established by comparison of the treated and comparator distributions, then in subsequent studies this criterion can be used to identify the numbers of people who appear to respond to tieatment in the actively treated and comparator oi placebo-treated groups and the significance of differences in response rate can be determined by straightforwaid statistical testing of those frequency When configured ds such, the characteristics of the response to treatment of the responder group can also then be examined, undiluted by the non-responder population. Neverthless, as can be appreciated, the above descriptions regarding such particulars like the specific comparators employed, the number and type of tests employed, the numbci or patients, the number of off- and on-treatments may all be modified to suit the particular needs of the clinician and to the specific affliction and/or drug being examined

[0024] Thus, as seen in one exemplary embodiment of the invention, the broadest aspect of the invention may be detailed as compiising a method, a method instantiated or executed on an electronic apparatus such as a computer, and/or a computer readable medium executing the following steps of identiiying a plurality of records relating to patients in a clinical database, said records compiising measurements for patients relating to tests administered during an off- treatment period and an on-trealment pcriod, identifying at least one test in said plurality of recoids relating to measurements of each individual during an off-tieatment period, identifying at least one test in said plurality of records relating to measurements of each individual during an on-treatment period, identifying a baseline measuiement of each individual during said off- tieatment period, performing a statistical distribution on said plurality of records to identify likelihood of said υπ-treatment and said off-treatment measurements exceeding said baseline so as to compare said measurements with said baseline, and selecting one oi more individuals ("responders"), wherein the selected individuals exhibit an impioved performance during a majority of the tests administered during the on-treatment period as compared to a best (e.g., fastest, strongest, etc.) response the test administered to the off-treatment period. However, as can be appreciated, the invention may take the form of a computer readable medium for executing the above detailed steps, or alternatively, may comprise a computer based system for selecting individuals based on responsiveness to a treatment, comprising: a memory module for storing patient measurements, and for storing at least a first set of instructions relating to the inputting and analyzing of said patient measurements, and a second set of instructions for outputting responder information from said patient measurements; a central processing unit for executing said first and second set of instructions; and an output module for outputting said responder information.

[0026] Accordingly, as seen in Figs. 1 , 2, and 3, is an exemplary depiction of the inventive process in: a generalized flow diagram (Fig. l )(showing steps 100 through 130, with optional resets for re-designing or re-conducting the process so as to reset undesirable results); a generalized flow diagram on one approach to generating a specialized, unique statistical distribution (e.g., step 1 14 of Fig. 1 ) used within the overall process (e.g., steps 100-130) in Fig. 1 ; and an exemplary hardware (apparatus) configuration (Fig. 3), upon which the exemplary flow processes in Figs. 1 and 2 are executed by the inventive software. The inventive software for executing the above described processes, and for analyzing inputted data, outputs useful information such as responder data. The inventive software and process may be embodied in computer any manner of readable code, and may be contained on any computer readable medium, such as a hard drive (whether PC based, or remote server), disk, CD, etc. When configured as such, the measurements of the patients P are formatted as signals that may be received by the apparatus of Figure 3 so that the inventive process and software may be transformed into useful outputs for a user. This outputted information may be received by the apparatus in order to be processed and analyzed by the inventive process for use by a user who may receive the outputted signals that have been formed by the steps described herein. As such, the technical effect is such that when the signals are processed in accordance with the above, the tangible, useful result is that clinical trials may be better planned and/or analyzed by researchers who may identify responders to a given treatment for an affliction of almost any nature in ways that were not available heretofore. In any case, in order to achieve this desirable result, it is to be emphasized that the included figures are merely illustrative, and may be reconfigured or revised in many different ways, as one skilled in the art may appreciate.

[0027] In a specific exemplary application of one embodiment of the present invention, a method of analyzing the treatment of an illustrative affliction, such as multiple sclerosis is provided. In such an example, the goal might be to employ (he general inventive process and software described herein to show the results of a completed clinical study, or otherwise structure a future clinical study that aims to identify respondβrs from a group of patients who receive a given exemplary treatment. In doing so, many indicators may be employed, but in the exemplary illustration indicated in the attached Appendices A, B, C, D and E (each of which is hereby explicitly incorporated by reference in their entireties), such indicators may be such specific measurements as increased walking speed in patients, or increased muscle tone or muscle strength in patients.

[0028] Thus, in the given exemplary affliction and clinical treatment depicted in Appendices A, B. C, D, and E, only a proportion of MS patients would typically be expected to have axons of appropriate functional relevance that are susceptible to these drug effects, given the highly variable pathology of the disease. Nevertheless, when the inventive process and software is employed in the manner described herein, and as broadly illustrated in Figs. 1 , 2, and 3, the innovative methodology identifies and characterizes the subset of patients who respond to the exemplary drug fampridine.

[0029] To this end, the present invention provides for a method of selecting individuals based on responsiveness to a treatment. In one embodiment, the method comprises identifying a plurality of individuals; administering a test to each individual prior to a treatment period; administering a treatment, including, but not limited to administering a therapeutic agent or drug, to one or more of the individuals during the treatment period; administering the test a plurality of times to each individual during the treatment period; and selecting one or more individuals, wherein the selected individuals exhibit an improved performance during a majority of the tests administered during the treatment period as compared to the test administered prior to the treatment period. In certain embodiments, the method may further comprise administering the test to each individual after the treatment period, wherein the selected individuals further exhibit an improved performance during a majority of the tests administered during the treatment period as compared to the test administered after the treatment period.

[0030] It is important to note that this embodiment selects subjects who show a pattern of change that is consistent with a treatment response, but does not define the full characteristics of that response. The criterion itself does not specify the amount of improvement nor does it specify that the improvement must be stable over time. For example, a progressive decline in effect during the course of the study period, even one resulting in speeds slower than the maximum non-treatment value, would not be excluded by the criterion; as a specific example, changes from the maximum non-treatment value of, respectively, +20%, +5%, + 1 % and -30% during the double blind tiealmcnl pci iod would quali fy as a i espouse under the criterion, but would actually show a net negative aveuigc change for the entn e periocl, poor stability and a negative endpoint Post-hoc analyses of studies discussed in gi eater detail below indicate that we may expect responders defined by consistency of effect also to demonstrate increased magnitude and stability of benefit Thus, as indicated in Appendices A, B, C, D, and E, the existence of a subset of patients who respond consistently to the drug can be suppoi ted by quantitative observations in the exemplary clinical studies discussed below

[0031] As further noted in the exemplary application of the inventive piocess and software on the illustrative clinical trial dcscribed in Appendices A, B, C. D, and E, before treatment, the subjects in these two trials exhibited average walking speeds on the TW25 measure of approximately 2 feet per second (ft/sec) This is a significant deficit, since the expected walking speed for an unaffected individual is 5-6 ft/sec Subjects in MS-F202 were selected for TW -25 walking time at sci eening of 8-60, which is equivalent to a range in speed of 0 42-3.1 ft/sec Variability of functional status is an inherent characteristic of MS, and this can be seen in repeated measurement of walking speed over the course of weeks or months At any of the three visits during the stable treatment period, 15-20% of placebo-treated subjects showed >20% improvement from baseline walking speed, a threshold chosen as one that is likely to indicate a true change in walking speed over background fluctuations A larger proportion of the Fampridine-SR treated subjects showed such improvements, but this difference was not statistically significant, given the sample size and placebo response rate

[0032] Given the often large variations in function experienced by people with MS, it is difficult for the subject or a tiamed observ er to separate a treatment-related improvement from a disease-related improvement without the element of consistency over time Consistency of benefit might therefore be expected to be a more selective measure of true treatment effect than magnitude of change Based on this rationale, the responses of the individual subjects in the MS- F202 trial were examined for the degree to which their walking speed showed improvement during the double-blind treatment penod and returned towaids pi e-treatment values after they were taken off drug, at fυllovv-up T Ins subject-by-subject examination yielded a subgroup of subjects whose pattern of walking speed over time appeared to be consistent with a drug response This led to the analysis illustrated in Figure 1 This coinpaies the placebo and Fampndine-SR heated groups with respect to the number of visits during the double-blind treatment period in which walking speed on the TW25 was taster than the maximum speed out ot all five of the non-treatment visits (tour visits prior to randomization and one follow-up visit after the drug treatment period) [0033] The placebo-treated group showed a clear pattern of exponential decline in numbers of subjects with higher numbers of "positive" visits. This is what would be expected from a random process of variability. In contrast, the pattern of response in the Fampridine-SR treated group strongly diverged from this distribution; much larger numbers of Fampridine-SR treated subjects showed three or four visits with higher walking speeds than the maximum speed of all five non-treatment visits and less than half of the expected proportion had no visits with higher speeds. These results indicate that there was a sub-population of subjects in the Fampridine-SR treated group that experienced a consistent increase in walking speed related to treatment.

[0034] This analysis suggests that a relatively highly selective criterion for a likely treatment responder would be: a subject with a faster walking speed for at least three (i.e., three or four) of the four visits during the double blind treatment period compared to the maximum value for all five of the non-treatment visits. The four visits before initiation of double-blind treatment provide an initial baseline against which to measure the consistency of response during the four treatment visits. The inclusion of the follow-up visit as an additional component of the comparison was found valuable primarily in excluding those subjects who did not show the expected loss of improvement after coming off the drug. These are likely to be subjects who happened by chance to have improved in their MS symptoms around the time of treatment initiation, but whose improvement did not reverse on drug discontinuation because it was actually unrelated to drug. Thus, incorporating the follow-up visit as part of the criterion may help to exclude false positives, if the TW25 speed remains high at follow-up.

[0035] As described in Example 5 in Appendix A, this responder criterion was met by 8.5%, 35.3%, 36.0%, and 38.6% of the subjects in the placebo, 10 mg, 15 mg, and 20 mg b.i.d. treatment groups, respectively, showing a highly significant and consistent difference between placebo and drug treatment groups. Given that there was little difference in responsiveness between the three doses examined, more detailed analyses were performed comparing the pooled Fampridine-SR. treated groups against the placebo-treated group. The full results of this analysis for study arc described in the following sections. These show that the responder group so identified experienced a >25% average increase in walking speed over the treatment period and that this increase did not diminish across the treatment period. The responder group also showed an increase in Subject Global Impression score and an improvement in score on the MSWS- 12. Thus, when utilizing the inventive process and software, it became possible to identify responders experienced clinically meaningful improvements in their MS symptoms, and treatment with fampridine significantly increased the chances of such a response. In doing so, a baseline was established showing compai ability among the respondert analysis groups, and then analyses were perfomed on the baseline demogiaphic variables, key neurological characteristics and the relevant efficacy variables at baseline. In general, the iesponder analysis groups were comparable for all deinogiaphic and baseline characteristics variables, with certain exceptions

[0036] Having demonstrated the clinical meaningfulness of consistently improved walking speeds during the double-blind period as a criterion for responsiveness, the question of the magnitude of benefit becomes of interest The observed differences between the fampridine responders and the placebo group for the functional variables in this study are exactly what we would expect to see in the functional vanables in an enrichment study where after a run-in period, only fampridme responders aic entered, followed by a washout and randomization to either placebo or fampridinc. The fampridine non-rcsponders, although providing no relevant efficacy information, do provide safety information regarding those individuals who are treated with fampridine but show no apparent clinical benefit As such, respondci analyses of these groups were performed

[0037] In one further excmplaiy embodiment, a method of selecting individuals based on responsiveness to a treatment is derived from executing a range disparity distribution and applying it in a clinical trial setting In this embodiment, a novel "range disparity" (RD) distribution (RDD) is used to compute the probability that a given number of items (such as patients) in one set tall outside the range, on a give measure, of all the items (patients) in another set. Application of this distiibxition to evaluation of data from a real clinical trial is described and demonstrates an efficient new form at response analysis As will be appreciated by those skilled in the art, many additional applications of the i ange disti ibution in clinical and other settings may be developed The follow ing discussion is also picscnted in Appends F later on hercin

[0038] The exemplaiy particulars of the fundamental pnnciple behind a range distribution may be described in the following rudimentaiy fashion Suppose that there aie three uuis, call them X, Y and Z Suppose urn Z contains 10 straws of slightly different lengths A referee selects five straws, places them into urn X and places the remaining tive straws into urn Y What is the probability distribution that a given number of straws in urn Y are longer than the longest straw in urn X?

• The piobability is 5 out of 10 for urn X to provide the longest straw. Similarly, there is a 5/10 chance that urn Y will have no straws laigci than the largest straw in urn X

• For urn Y to have exactly one straw larger than the largest straw in urn X o urn Y must first have the largest straw (a 5/ 10 chance), o the 5 straws in urn X must he the largest among the remaining 9 straws (a 5/9 chance).

So the probability for urn Y to have exactly one straw larger than the largest straw in urn X is x 5/10 x 5/9.

• For urn Y to have exactly two straws larger than the largest straw in urn X, urn Y must first have: o the largest straw to begin with (a 5/10 chance); o the second largest straw among the remaining 9 (a 4/9 chance); o the 5 straws in urn X must be largest among the remaining 8 straws (a 5/8 chance).

So the probability for urn Y to have exactly two straws larger than the largest straw in urn X is x 5^ 0 x 4/9 x 5/8 = 5 -10 x 5/9 x 4/8

• Continuing this logic, if we let the random variable T represent the number of straws in urn Y that are larger than the largest straw in urn X the we obtain the following distribution :

As another example, suppose the Z u hrans 8-straws of different length, 5 of which are placed into urn X and 3 into urn Y. What is the probability distribution that a given number of straws in urn Y arc longer than the longest straw in urn X? By the equivalent logic described above, we obtain the following distribution :

Using several combinations of stiaws in urn X and inn Y, the pioblem can be generalized foi uin X to contain S-straws and Y urn to contain T-straws This leads to the following definition

Definition 1 Let N repiesent the set of positive integers A random variable Y lias the disti ibution which we will call the Range Disparity Distribution (RDD) when (foi S and T ε N and Y e 0 0 N such that 0 < Y < T)

This leads to the coi i csponding cumulative distribution function F(y)

While the pieceding discussion supplies the piobability disti ibution for the number of cases where items from X exceed the range of the items fiom Y, the same considerations will cover the opposite case the number of cases where the items rrom X fall below the iange of the items from Y

[0039] This disti ibution has numerous potential applications for example, in a clinical trial where measurements of a particular aspect of disease show essentially random variation with time. In such a case, we may be constrained (for example by clinic visit schedules) to obtain only a small sample of measurements from each patient over the course of a baseline period and a small sample of measurements over a treatment period. The RDD provides a simple and effective way to identify individuals who show an unexpected range-shift in either the positive Oi negative direction, indicating either a consistent benefit or a consistent worsening that is temporally associated with the treatment. In addition to making between group comparisons, we can compare the distribution of changes in the placebo group to the expected RDD to identify and measure any temporal changes due to factors such as the placebo effects and natural disease piogression or remission.

[0040] Consistency of benefit from treatment would be expected to be a more effective measure of response (i.e. of causality) than simply examining the magnitude of change between the average baseline visit and the average treatment visit. This is because a meaningful, consistent benefit may be small in magnitude and a large random deviation, occurring during any individual measurement, can have a substantial but ultimately meaningless effect on the average value across a small number of sample measurements.

|0041 ] Example 1 - Theoretical basis: Assuming a clinical trial such that for each patient there are S off-drug measurements of a particular affected function and T on-drug measurements. Let Y ieprescnt the number of on-drug measurements that are better (e.g. more normal) than the best off-drug measurement. Assume Y follows the range disparity (RD) distribution. For example, if there arc S=5 off-drug visits and T=5 on-drug visits then the probability distribution of Y, is:

[0042] This distribution implies that, if the active treatment has no effect we would expect the proportion of patients who experience a consistent improvement, reflected by 4 or 5 on-drug measurement better than the best off-drug measurement, to be about 2 5% The null hypothesis that the gioups arc equal with regard to the proportion of subjects with consistent improvement can be tested using a standard test such as Fisher's exact test, a chi-scμiare test, or for stratified samples (e.g., by study center) the Cochran-Mantel-Haeπszel test. Signi ficant departures from this expected frequency in the active treatment group, but not the placebo group, would lead us to conclude that the treatment and placebo groups are different. Significant differences between all three distributions (active treatment, placebo, and expected RD), would indicate a treatment effect superimposed on a temporal change due to other factors.

[0043] Hence, the identification of a consistent response as represented by 4 or 5 of the on-drug measurements as better than the best off-drug measurement provides a particularly clear criterion for a responder analysis. A traditional responder analysis would establish an arbitrary level of average change (e.g. 10%, 20%) above which a trial subject would qualify as a responder. Generally, there is no clear clinical or statistical justification for such a criterion and no a priori method for its estimation. On the other hand, a criterion of consistency based on the RDD can be clinically meaningful (being based on consist relationship to treatment over time), statistically appropriate (based on a threshold of statistical probability, here approximately 2.5% for a one-sided criterion.) and it can be calculated a priori, given the trial design.

|0044| Below is a brief outline of a general approach to determine appropriate parameters for a responder criterion based on the concept of consistency across measurements. A general approach to determine an appropriate response criterion for a clinical trial might be derived as follows:

Let,

X_is (i=1 ,2,, ..., I and s=1 ,2, ...S) represent the s^th off-drug measurement for patient i .

Y_it (i=1 ,2,. ..., I and t=1 ,2, ...T) represent the t^th on-drug measurement for patient i . Assumptions:

• Each X and Y measurement addresses the same outcome variable: Z (we use X and Y to differentiate measurements during different time-periods: off-drug and on-drug).

• Initially assume no treatment effect and that there is no longitudinal effect on the outcome measure. That is to say that over time, there is at best, negligible within-patient correlation. If such an effect exists, it will become apparent in the analysis itsel f.

Set up a consistency criterion C which is a relation (p) between the off-drug measurements and each on-drug measurement such that:

and compute the number of on-druy, visits that fulfill the criterion

choose a value λ < T such that a responder criterion is defined as:

For clinical trials, a good rule of thumb is to choose λ such that the theoretical responder rate is no larger than 5Vo, i.e.:

0 < [P(C_iR)=1 ] ≤ 0.05

[0045] Example 2 - Practical experience: The following is based on data from a clinical trial that examined the effects of a novel treatment in improving walking speed in patients diagnosed with a chronic disease and was designed with 5 off-drug and 4 on-drug assessments of walking speed. Subjects were randomized to receive active drug or placebo in a 3:1 ratio. For a given patient, if we let Y represent the number of on-drug measured walking speeds that are faster than the fastest off-drug walking speed and assume Y follows the RDD we have:

Table 1 . Table showing the theoretical distribution of on-drug visits with faster walking speeds than the fastest off-drug walking speed using the RDD.

[0045] Applying the general approach to determine an appropriate response criterion, response to treatment was defined as a faster walking speed in at least 3 of the 4 on-drug visits compared to the fastest speed measured during the 5 off-drug visits. There were 205 intcnt-to- treat patients included in the primary efficacy analysis (47 placebo and 158 active treatment). Table 2 below summarizes the key study lesυlt.

Table 2. Table showing the percentage of responders, selected for consistent improvement in walking speed in the placebo-treated and active-drug treated groups. P-value calculated from the Cochran-Mantel-Haenszel test, controlling for study center.

[0047] As can be seen, the placebo responder rate (8.5%) was very close to the theoretical responder rate of about 5%. Indeed, when we examine the frequency distribution for the placebo-treated group in Graph A, below, we see that the observed distribution of better on- drug measurements was similar to that expected from the RDD, thereby suggesting negligible temporal or placebo effects in this trial. On the other hand, the distribution of measurements in the actively treated group was significantly different from both the placebo and the theoretical distributions. In particular, there were large differences in the proportion of subjects showing no measurements faster than the fastest off-drug measurement and showing 3 or 4 faster visits. This indicates that active treatment but not placebo treatment is associated with more consistent improvement than would be expected from the RDD, and that our selection of the response criterion based on statistical probability is reasonable in practice.

[0048] Figure 4 (a): Histogram to show the proportion of subjects in the two treatment groups who experienced a given number of walking assessments during treatment that were faster than the fastest speed measured during the off-treatment period. These distributions arc compared to the expected RD probability distribution.

[0049] The utility of this form of response analysis is shown both by the differentiation of treatment and control groups and by the ability to show that, in the absence of active treatment, there was no significant independent shi ft in the placebo group that would indicate treatment-independent changes related to time or to placebo-effects.

[0049] The application of this criterion for "consistent response analysis" allows very efficient sampling. This is shown by comparing three forms of analyzing the data from this study in Figures 4 (b)-(d). Simply by examining the distribution of mean changes between baseline and treatment periods in a traditional quantitative comparison (in Figure 4(c)) we see a trend for improvement in the drug-treated group, and we would expect such a difference to be resolved with statistical significance in a much larger study). However, in this study the difference was not significant by ANOVA A traditional response analysis, setting a threshold of 15% linpiovemcnt (Figure 4 (c)) shows again a clear favoi ablc trend, with many moie "i cspondci s' in the active gioup, but tins is not statistically significant with the sample size available (using the Cochran-Mantcl Haenszel test) Similar iesults are achieved with other arbitiary icsponse thresholds, e g. 10% or 20% Applying the "'consistent lesponse' criterion, we see a highly statistically significant response with the available sample size (Figure 4(d), Table 2) Not only is the overall analysis rendered more sensitive by the consistent response criterion, but this approach, unlike the other two, also allows us a) to show that the placebo response rate is not significantly different fiom that expected by random variability (Figure 4 (a), Table 2), and b) to know before the trial that the expected false-positive rate for the criterion is approximately 5% (Table 1) based on the RD probability distribution

[0051] Figure 4(b) Distribution of changes in average walking speed between the baseline, pre-tieatmcnt period and the double-blind treatment penod for patients randomized to either placebo treatment or active treatment Although there appeals to be a difference in mean changes between treatment gioups, this was not statistically significant based on ANOVA.

[0052] Figure 4 (c) Applying a traditional responder analysis to the data in Figuie 4 (b), with a threshold for "response" set at >15% impiovement This shows that the distribution of changes among non-responders in the drug-treated group is very different from that of the placebo group, indicating the presence of significant numbers of false negatives among non- responders and false positives among respoπders A total of 7 placebo-tieated patients registered as responders, for a 14 8% false-positive rate in that group The response rate in the drug-tieated group was 44 2% The drug-placebo response differential was therefoie 29 4%, but this was not statistically significant Clearly, the threshold chosen for the response definition will affect the numbers of responders in both treatment gioups but would not change the arbitrary nature of the division between icsponders and non-responders

[0053] Figure 4(d) Applying the consistent (lepeated measures) response analysis to the same data from Figure 4 (b) selects out a non-responder population that is close to the placebo-treated group in its distribution Only 4 subjects in the placebo group rcgistered as lesponders, for an 8 5% false positive rate The response rate in the daig-treated group was 37 2% The drug-placebo response differential was therefore 28 7%, similar to the 29 3% seen with the traditional responder analysis approach shown in Figure 4 (b) However, in this case there was a lower frequency of false positives in the placebo gioup, and the difference between treatment group response rates was statistically significant (p<0 001 , Table 1 ) [0054] Example 3 : The application of this distribution is particularly powerful in the context of a repeated measures response analysis of the kind provided by Example 2. However, it may be useful in various simpler situations, for example, in a case of industrial product sampling. There might be a suspicion that plant A is producing items with a breaking strength that is lower than those from plant B. For destructive testing of items from the two plants we would likely want to minimize the sample size. If we sampled 5 out of 100 items from the next production run at each plant and determine that the breaking strength of more than 2 of these items from plant A falls below the range of the 5 tested from plant B we would have support for the suspicion regarding a difference between the plants. More specifically, we would know that there is less than a 2.5% chance, on the basis of random variability (Example 1 ), that 4 or 5 of the samples from A would fall below the failure range for those from plant B.

[0055] The range disparity distribution, therefore describes the expected behavior of two small samples from a common population. Specifically, it defines the probability that any given number of values in one sample from that population will fall outside the range of values in the other sample, in either the positive or negative direction. This distribution can be applied to novel forms of small-sample statistical analysis. An example of application to a repeated measures response analysis in a clinical trial is described. The definition of a consistent response, based on the sample range disparity distribution, improves the sensitivity as well as the statistical and clinical meaningfulπess of such an analysis.

[0056] Example 4: In addition, the method, system and software of the present invention was utilized in the testing of Fampridinc-SR on walking in people with multiple sclerosis (MS) during a Phase 3 trial, the results of which were announced on September 25, 2006. In particular, this Phase 3 clinical trial of Fampiϊdine-SR on walking in people with multiple sclerosis (MS) was a confirmation of the pertinence of the inventive approach. In utilizing the method, system and software of the present invention, statistical significance was achieved on all three efficacy criteria defined in the Special Protocol Assessment (SPA) by the Food and Drug Administration (FDA). As a result of utilizing the inventive techniques, a significantly greater proportion of people taking Fampridine-SR had a consistent improvement in walking speed, the study's primary outcome, compared lυ people taking placebo (34.8 percent vs. 8.3 percent) as measured by the Timed 25-Foot Walk (p less than 0.001 ). In addition, the effect was maintained in this study throughout the 14-week treatment period (p less than 0.001) and there was a statistically significant improvement in the 12-ltem MS Walking Scale (MSWS- 12) for walking responders vs. non-responders (p less than 0.001 ). The average increase in walking speed over the treatment period compared to baseline was 25.2 percent tor the dπig-responder group vs. 4.7 percent for the placebo group. Increased response rntc on the Timed 25-Foot Walk was scan across all four major types of MS. In addition, statistically significant increases in leg strength were seen in both the Fampridine-SR Timed Walk responders (p less than 0.001 ) and the Fampridine-SR Timed Walk non-responders (p=0.046) compared to placebo.

[0057] Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore the spirit and scope of the appended claims should not be limited to the description and the preferred versions contain within this specification.

Appendix A

The below text is reproduced merely for illustrative purposes, was excerpted from US Pat. Application No 1 1/102,559, the entirety of which is hereby incorporated by reference.

EXAMPLE 5

This example provides an embodiment of a method of treating subjects with a sustained release fampridine formulation and a responcler analysis of the present invention. This was a Phase 2, double-blind, placebo-controlled, parallel group, 20-week treatment study in 206 subjects diagnosed with Multiple Sclerosis. This study was designed to investigate the safety and efficacy of three dose levels of Fampridine-SR, 10 mg b i d., 15 nig b.i.d., and 20 mg b.i.d. in subjects with clinically definite MS. The primary efficacy endpoint was an increase, relative to baseline, in walking speed, on the Timed 25 Foot Walk. Secondary efficacy measurements included lower extremity manual muscle testing in four groups of lower extremity muscles (hip flexors, knee flexors, knee extensors, and ankle dorsi flexors); the 9-HoIe Peg Test and Paced Auditory Serial Addition Test (PASAT 3"); the Ashworlh score for spasticity; Spasm Frequency/Severity scores; as well as a Clinician's (CGI) and Subject's (SGI) Global Impressions, a Subject's Global Impression (SGI), the Multiple Sclerosis Quality of Life Inventory (MSQLI) and the 12-Item MS Walking Scale (MSWS- 12).

At the first visit (Visit 0) subjects were to enter into a two-week single-blind placebo run-in period for the purpose of establishing baseline levels of function. At Visit 2 subjects were . to be randomized to one of four treatment groups (Placebo or Fampridine-SR 10 mg, 15 mg, 20 mg) and begin two weeks of double-blind dose-escalation in the active drug treatment groups (B, C and D). Group A were to receive placebo throughout the study. Subjects in the 10 mg (Group B) arm of the study took a dose of 10 mg approximately every 12 hours during both weeks of the escalation phase. The 15 mg (Group C) and 20 mg (Group D) close subjects took a dose of 10 mg approximately every 12 hours during the first week of the escalation phase and titrated up to 15 mg b.i.d. in the second week. Subjects were to be instructed to adhere to an "every 12 hour" dosing schedule. Each subject was advised to take the medication at approximately the same time each day throughout the study; however, different subjects were on differing medication schedules (e.g., 7 AM and 7 PM; or 9 AM and 9 PM). After two weeks, the subjects were to return to the clinic at Visit 3 for the start of the stable dose treatment period. The first dose of the double-blind treatment phase at the final target dose (placebo b.i.d. for the Group A, 10 mg b.i.d. for Group B, 15 mg b.i.d. for Group C, and 20 mg b.i.d. for Group D) was taken in the evening following Study Visit 4. Subjects were to be assessed five times during the 12-week treatment period . Following the 12-week treatment phase there was to be a one-wcck clown titration starting at Visit 9. During this down-titration period, group B was to remain stable at 10 mg b.i.d. and Group C was to be titrated to 10 mg b.i.d., while group D was to have a change in the level of dose during the week (15 mg b.i.d. for the first three days and 10 mg b.i.d. for the last four days). At the end of the down titration period at Visit 10, subjects were to enter a two-week washout period where they did not receive any study medication. The last visit (Visit 1 1) was to be scheduled two weeks after the last dosing day (end of the downward titration). Plasma samples were collected at each study site visit other than Study Visit 0.

The primary measure of efficacy was improvement in average walking speed, relative to the baseline period (placebo run-in), using the Timed 25 Foot Walk from the Multiple Sclerosis Functional Composite Score (MSFC). This is a quantitative measure of lower extremity function. Subjects were instructed to use whatever ambulation aids they normally use and to walk as quickly as they could from one end to the other end of a clearly marked 25-foot course. Other efficacy measures included the LEMMT, to estimate muscle strength bilaterally in four groups of muscles: hip flexors, knee flexors, knee extensors, and ankle dorsiflcxors. The test was perfonncd at the Screening Visit and at Study Visits 1 , 2, 4, 7, 8, 9 and 1 1 . The strength of each muscle group was rated on the modified BMRC scale: 5 = Normal muscle strength; 4.5= Voluntary movement against major resistance applied by the examiner, but not normal; 4= Voluntary movement against moderate resistance applied by the examiner; 3.5= Voluntary movement against mild resistance applied by the examiner; 3= Voluntary movement against gravity but not resistance; 2= Voluntary movement present but not able to overcome gravity; 1 = Visible or palpable contraction of muscle but without limb movement; and 0= Absence of any voluntary contraction. Spasticity in each subject was assessed using the Ashworth Spasticity Score. The Ashworth Spasticity Exam was performed and recorded at the Screening Visit and at Study Visits 1 , 2, 4, 7, 8, 9 and 1 1.

Protocol Specified Responder Analysis. To supplement the primary analysis, a categorical "responder" analysis was also conducted. Successful response was defined for each subject as improvement in walking speed (percent change from baseline) of at least 20%. Subjects who dropped out prior to the stable dose period were considered non-responders. The proportions of protocol specified responders were compared among treatment groups using the Cochran- Mantel-Haenszel test, controlling for center.

Post hoc analysis of this study suggested that a relatively highly selective criterion for a likely treatment responder would be a subject with a faster walking speed for at least three visits during the double blind tictitment period as compared to the maximum value among a set of five non-treatment visits (foui before treatment and one after discontinuation of treatment). The four visits before initiation of double-blind treatment provided an initial baseline against which to measure the consistency of response during the four double-blind treatment visits. The inclusion of the follow-up visit as an additional component of the comparison was useful primarily in excluding those subjects who may be false positives, i.e., did not show the expected loss of improvement after coming off the drug. Treatment differences in the proportion of theses post hoc responders were analyzed using the Cochran-Mantel-Haenszel (CMH) test, controlling for center.

To validate the clinical meaningfulness of the post hoc responder variable, (post hoc) responders were compared against the (post hoc) non-responders, on the subjective variables: (i) Change from baseline in MSWS- 12 over the double-blind; (ii) SGl over the double-blind; and (iii) Change from baseline in the CGl over the double-blind; to determine if subjects with consistently improved walking speeds during the double-blind could perceive improvement relative to those subjects who did not have consistently improved walking speeds. For the subjective variables, differences between responder status classification (responder or non- responder) were compared using an ANOVA model with effects for responder status and center.

Results. A total of 206 subjects were randomized into the study: 47 were assigned to placebo, 52 to 10 mg bid Fampridine-SR (10 mg bid), 50 to 15 mg bid Fampridine-SR (15 mg bid), and 57 to 20 mg bid Fampridine-SR (20 mg bid). The disposition of subjects is presented in Table 5 below.

Table 5 Summary of subject disposition (all randomized population)

Note: Percentages are based on the number of randomized subjects. All 206 randomized subjects took at least one dose of study medication and were included in the safety population. One subject (subject# 010/07 I O mg bid group) was excluded from the ITT population (lost to follow-up after 8 days of placebo run-in). A total of 1 1 subjects discontinued from the study.

The population consisted of 63.6% females and 36.4% males. The majority of the subjects were Caucasian (92.2%), followed by Black (4.9%), Hispanic (1.5%), those classified as 'Other' (1.0%), and Asian/Pacific Islander (0.5%). The mean age, weight, and height of the subjects were 49.8 years (range: 28-69 years), 74.44 kilograms (range: 41.4- 145.5 kilograms), and 168.84 centimeters (range: 137.2-200.7 centimeters), respectively. Most of the subjects (52.4%) had a diagnosis type of secondary progressive with about equal amounts of relapsing remitting (22.8%) and primary progressive (24.8%) subjects. The mean duration of disease was 12.00 years (range: 0.1-37.5 years) while the mean Expanded Disability Status Scale (EDSS) at screening was 5.77 units (range: 2.5-6.5 units). The treatment groups were comparable with respect to all baseline demographic and disease characteristic variables.

Results for the key efficacy variables at baseline for the ITT population are further summarized in Tabic 6 below.

Table 6 Summary of key efficacy variables at baseline (ITT population)

One subject did not have a baseline value.

With respect to the 205 subjects in the ITT population, mean values for baseline walking speed, LEEMT, SGl, and MSWS-12 were approximately 2 feet per second, 4 units, 4.5 units, and 76 units, respectively. The treatment groups were comparable with iespect to these variables as well as all the other efficacy variables at baseline. Descriptive statistics for the average walking speed (ft/sec) by study day based υn Hie Timed 25-Foot Walk are presented in Table 7 and Figure 2. The timed 25 foot walk showed a trend toward increased speed during the stable dose period for all three dose groups, though the average improvement declined during the treatment period. Table 7 Average walking speeds (ft/sec) by study day (observed cases, ITT population)

#: The treatment sample sizes presented in the figure legend represent the number of ITT subjects. Sample sizes at individual time points may be smaller than those in the ITT population due to dropouts or missed assessments.

During double-blind treatment, all the Fampridine-SR groups exhibited mean walking speeds between 2.00 and 2.26 feet per second, while the mean value in the placebo group was consistently about 1.90 feet per second. It should be noted that, at the third stable-dose visit, both the 10 mg bid and 20 nig bid gioup means dropped-off from what would be expected under the assumption that treatment benefit is consistent over time. This may or may not have been due to chance; further studies should proλ'ide additional evidence for either case. After double-blind medication was discontinued, all the treatment groups converged to approximately the same mean value at follow-up.

Results for the primary efficacy variable (percent change in average walking speed during the 12-week stable dose period relative to baseline based on the 25-foot walk) are summarized in Figure 3. The timed 25 foot walk showed a trend toward increased speed during the stable dose period for all three dose groups, though the average improvement declined during the treatment period, as shown in Figure 3. The mean percent changes in average walking speed during the 12- week stable dose period (based on adjusted geometric mean change of the log-transformed walking speeds) were 2.5%, 5.5%, 8.4%, and 5.8% for the placebo, 10 mg bid, 15 mg bid, and 20 mg bid groups, respectively. There were no statistical differences between any Fampridine-SR groups and the placebo group Results foi the piorocol specified i esponder analysis (subiccts with average changes in walking speed during the 12 weeks of stable double-blind treatment of at least 20%) aie summarized in Figui c 4. The percentages of subjects with average changes in walking speed during the 12-week stable dose period of at least 20% (pre-defined responders) were 12 8%, 23.5%, 26 5%, and 16 1 % for the placebo, 10 mg bid, 15 mg bid, and 20 mg bid groups, respectively There were no statistically significant differences between any of the Fampridme- SR groups and the placebo group

Descriptive statistics for the average overall Lower Extremity Manual Muscle Testing (LEMM'l ) by study day aie presented in Table 8 and in Figure 5 Table 8. Average overall LEMMT by Study Day

#: The treatment sample sizes presented at individual time points may be smaller than those in the ITT population due to dropouts or missed assessments.

During double-blind treatment, all the Fampridine-SR giυups exhibited a numerical pattern of larger mean LEMMT scores than placebo (except the 20 mg bid group at the 2^nd stable dose visit) After double-blind medication was discontinued, with the exception of the 15 mg bid group, all the group means were lowci than they were at baseline

Results for the average change in LEMMT during the 12-week stable dose period lelutivc to baseline aie suinmarizcd in Hguie 6 The mean changes in overall LEMMT during the 12- week stable dose period were -0 05 units, 0 10 units, 0 13 units, and 0 05 units for the placebo, 10 mg bid, 15 mg bid, and 20 mg bid gioups, iespectively Improvements in LEMMT were significantly greater in the 10 mg bid and 15 mg bid groups compared to the placebo group, there was no significant difference between the 20 mg bid group and the placebo group

No statistically significant differences were detected among treatment group based on any of the other secondary efficacy variables, as shown in Table 9

Table 9. Changes from baseline during the 12-week stable dose period in selected secondary efficacy variables (observed cases, ITT population)

Note: The treatment sample sizes presented in the treatment heading represent the number of ITT subjects. Sample sizes for individual variables may be smaller due to dropouts or missed assessments.

Note: For each variable, the p-values (versus placebo) are Dunnett-adjusted. While pre-planned analyses of the pnmaiy efficacy cndpoint piovided insufficient evidence of treatment benefits foi any of the Fampudme-SR doses, subsequent analysis revealed the existence of a subset of subjects who responded to the drug with clinical meaningfulness These subjects exhibited walking speeds while on drug that were consistently bettet than the fastest walking speeds measured when the subjects were not taking active drug

The post hoc iesponder iates based on consistency of improved walking speeds were significantly higher in all three active dose groups (35, 36 and 39%) compaied to placebo (9%, p<0.006 for each dose group, adjusting foi multiple compai isons) as shown in I igure 7

Given that therc was little difference in lesponsiveness between the tlu ce doses examined, more detailed analyses were perfoimed comparing the pooled Fampridine-SR tiealed groups against the placebo-treated group Figuie 8 summarizes, for the placebo and the pooled Fampudme-SR gtoup, the percentage of post hoc responders The number of subjects who met he post hoc responder ci iterion in the pooled Fampridine-SR treated gioup was 58 (36 7%) compared to 4 (8 5%) in the placebo-treated gioup, and this diffcience was statistically significant (ρ<0 001 )

To validate the clinical meaningfulness of the post hoc i esponder variable, the 62 iesponders (58 fampndine and 4 placebo) were compared against the 143 non-icsponders (100 fampndine and 43 placebo) on the subjective variables to determine if subjects with consistently impioved walking speeds during the double-blind could perceived benefit relative to those subjects who did not ha\ e consistently impioved walking speeds The iesults aie summarized in Figure 9 and indicate that consistency in walking speed had clinical meaningfulness foi the subjects in this study since the responders had (over the double-blind period) significantly better changes from baseline in MSWS- 12 and significantly better subjective global scores In addition, the rcspondcis were iatcd marginally better than the non-respondcis by the clinicians during the double-blind Thus responders experienced clinically meaningful improvements in their MS symptoms, and tientinent with fampndine significantly increased the chances of such <ι response

To establish baseline comparability among the i esponder analysis gioups, analyses were performed on the baseline demographic variables, key neurological characteristics and the relevant efficacy variables at baseline In general, the responder analysis groups were comparable for all demographic and baseline characteristics variables

Having demonstrated the clinical meaningfulness of consistently improved walking speeds during the double-blind as a ciiterion for responsiveness, the question of the magnitude of benefit becomes of intciest. The obser ved differences between the fampridine responders and the placebo gioup ioi the functional vanables in this study are exactly what we would expect to see in the functional variables in an enrichment study where after a run-m pci iod, only fnmpridine responders ai e entered, followed by a washout and landomization to either placebo or fampridine The fampridine non-responders, although providing no relevant efficacy information, do piovidc safety information regarding those individuals who aie treated with fampridine but show no apparent clinical benefit As such, rcsponder analyses of these gioups wer c performed

With respect to magnitude of benefit, Figure 10 and Table 12 below summarizes the percent changes in walking speed at each double-blind visit by rcsponder analysis giouping The mean improvement foi the fampridine responders during the double-blind acioss 14 weeks ot treatment ranged from 24 6% to 29 0% compared to 1 7% to 3 7% for the placebo gioup, this was highly significant (p<0 001) at every visit Although pioviding no relevant efficacy information, results for the fampi idine non-responders are also illustrated and show that there was, and could be, some worsening in walking speeds after 12-weeks when a non-responder is treated with fampiidine The imptovement was stable (± 3%) across 14 weeks of treatment, and was associated with improvement in two global measures (Subject Global Impression and Multiple Sclerosis Walking Scale- 12) The four placebo responders showed a 19% lmpiovement in walking speed but there were too few subjects in this group for meaningful statistical comparison Response status was not significantly related to baseline demographics, including type or seventy of MS Advcise events and safety measures were consistent with pievious experience foi this drug

Table 12. Siimmai y of percent change in Walking Speed at each double-blind visit by i esponcler analysis grouping.

ABBREVIATIONS: FR=Fampridine Kcsponders; FNR=Faιiipridinc Non-rcsppiiders.

**: Significantly better than placebo and fampridine non-responders (p < 0.001 for each).

*: Significantly better than fampridine non-responders.

#: The treatment sample sizes presented in the figure legend represent the number of ITT subjects. Sample sizes at individual time points may be smaller due to dropouts or missed assessments.

^Λ: P-values from t-tcsts of the least-squares means using the mean square error via an

ANOVA model with effects for responder analysis grouping and center.

Figure 1 1 and Table 13 summarize the changes in LEMMT at each double-blind visit by responder analysis grouping. The mean improvement for the fampridine responders during the double-blind ranged from 0.09 to 0.18 units compared to -0.04 units at each visit for the placebo group; this was significant at every visit except the second stable dose visit (p=0. I O6). Although providing no relevant efficacy information, results for the fampridine non-responders are also illustrated and show that there was, and could be, some significant improvement in leg strength when non-responder is treated with fampridine. This suggests that although a clinically meaningful response can be linked to about 37% of subjects treated with Fampridine-SR, additional subjects may have functional improvements on variables other than walking speed. Table 13. Summary of percent change in LEMMT at each double-blind visit by responder analysis grouping.

ABBREVIATIONS: FR=Fampridine Responders; FNR=Fampridinc Non-responders.

**: Significantly better than placebo and fanipridine non-responders (p < 0.001 for each).

*: Significantly better than fanipridine non-responders.

#: The treatment sample sizes presented at individual time points may be smaller than those in the ITT population due to dropouts or missed assessments. Treatment sample sizes presented in the figure legend represent the number of ITT subjects. Sample sizes at individual time points may be smaller due to dropouts or missed assessments.

ANOVA model with effects for responder analysis grouping and center.

Figure 12 and Table 14, below, summarize the changes in Overall Ashworth Score at each double-blind visit by responder analysis grouping The mean reduction fr om baseline (indicative of improvement) for the fampiidinc responders during the double-blind ranged from -0.18 to - 0.11 units compared to -0 1 1 to -0 06 foi the placebo group The fampridine responders were numerically superior to placebo but there was insufficient evidence to detect significant differences Although appearing to provide little relevant efficacy information, results for the fampridine non-responders arc also illustiated

Table 14. Summary of change in overall Ashwoi th score at each double-blind visit by responder analysis grouping.

ABBREVIATIONS: FR=Fampi idine Rcsponder s; FNR=Fampridine Non-responders.

**: Significantly better than placebo and tampridine non-responders (p < 0.001 for each).

*: Significantly better than fanipridine non-responders.

#: The treatment sample sizes pi esented at individual time points may be smaller than those in the ITT population due to dropouts or missed assessments.

^Λ: P-values from t-tests of the least-squares means using the mean square error via an

ANOVA model with effects for responder analysis grouping and center.

Adverse events most commonly reported prioi to treatment were accidental injury, reported by 12 (5 8%) subjects, nausea, ieported by 9 (4 4%) subjects, and asthenia, diarrhea, and pai esthesia, each reported by 8 (3 9%) subjects Six (2 9%) subjects also ieported headache, anxiety, dizziness, diarrhea, and penphciul edema These adverse events are indicative of the medical conditions affecting people with MS

Conclusions The data does not appeal to support cither a number ot anecdotal ieports or expectations from preclinical pharmacology that doses higher than about 10 to 15 nig b i d , and even about 10 mg b i d , should be associated with gi cater efficacy The data presented below in Table 15 support this, based on the new iesponder analysis methodology Table 15. Comparison of 10 mg vs. 15 mg among Responders

* For the average change in the MSWS- 12, a negative score is indicative of subjective improvement.

A responder analysis based on consistency of improvement provides a sensitive, meaningful approach to measuring effects on the timed 25 foot walk and may be used as a primary endpoint for future trials. This data suggest that for responsive subjects (approximately 37%), treatment with fampridine at doses of 10-20 mg bid . produces substantial and persistent improvement in walking.

Efficacy. There are no notable differences between 10 mg bid and 15 mg bid among subjects who respond to drug. In fact, the largest difference, favors the 10 mg bid group (see MSWS-12 result).

Safety. With respect to safety, there are three considerations: There was an apparent decline below baseline walking speed at the last visit on drug in the fampridine non-responders in the 10 mg bid and 20 mg bid groups, but not the 15 mg bid group. This may or may not be significant, but is not clearly dose related. There was an apparent rebound effect, with walking speed dropping below baseline, among fampridine treated subjects at the two week follow-up visit; this occurred in the 15 and 20 mg but not the 10 mg bid group. Serious AE's were more frequent in the 15 mg and 20 mg bid groups 10% and 12% rates vs. 0% rate in 10 mg bid and 4% in placebo groups. This may or may not be significant, but the risk of potentially related SAEs, particularly seizures appears to be dose-related from all available data and based on mechanism of action. Based on this data, it would appear that a 10 mg bid dose is preferred because of its favorable risk to benefit ratio compared with the 15 and 20 mg doses.

Appendix B

Fig. 1

Fig 2

Fig. 3

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Fig. 5

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Fig. 10

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Fig 12

APPENDIX C

METHODS

Figure 1 Study Design

A total of 206 subjects were eniolled in a 24-center, double-blind, placebo-controlled trial and randomized to one of four treatment groups. Fampridine (sustained release formulation) 10, 15, 20mg BID oi placebo A placebo run-in (2 wks) was followed by dose escalation (2 wks), stable tieatmcnt period (12 wks), down-titration (J wk) and follow-up evaluation (2 wks)

Inclusion Criteria

18-70 yr with definite MS (as defined by McDonald⁶), with adequate cognitive function and able to perform required study procedυies, including a Timed 25-Foot Walk twice (requued i ange to complete test at scieening 8 to 60 sec)

Outcome Measures

MS Functional Composite

Timed 25-Foot Walk

9-Hole Peg Test

Paced Auditoiy Serial Addition Test (PASAT)-3" Lower Extierruty Manual Muscle Testing (LEMMT Ashworth Score Clinician Global Impression (CGI) Subject Global Impression (SGI)

Multiple Sclerosis Quality of Life Inventory (MSQLI

12-Itcm Multiple Sclerosis Walking Scale (MSWS-12)⁷

Response Criterion for Consistency of I mprovement

Consistency of improvement in walking speed was defined (post hoc) as achieving walking speed during at least three (i.e. the majority) of the four "on drug" visits that was faster than the maximum speed measured din ing the five "off-drug" visits (four prior, one follow-up). The selection of this criterion was supported by observation of the distribution of faster "on drug" visits between the fampridine and placebo-treated groups (Figure 2)

Figure 2. Histogram to show the proportion υf subjects with a given number of "on drug" visits in which they achieved faster walking speed than the fastest of their five "off drug" visits. Fampridine-treated subjects showed more cases in which there were 3 or 4 faster on drug visits and less cases with no visits faster. The distribution of visits foi the placebo-treated group is close to that predicted for sampling of random variability from visit to visit.

Statistical Analysis

To determine if subjects with consistently improved walking speeds experienced meaningful improvements, statistical analyses were performed on two subjective variables (average SGI during the double-blind and the average change from baseline in MSWS-12 over the double-blind). Differences between response classifications (responders, vs. non-responders) were compared using an ANOVA model with effects for response classification and center.

The proportion of subjects with consistent improvements in walking speed (based on the retrospective definition) was analyzed by the Cochran-Mantel-Haeπszel (CJv1H) test, controlling for center. For each dose group p-values (versus placebo) were Bonferroni- adj usted.

RESULTS

Table 1. Subject Disposition

Baseline Demographics

There were no significant differences in baseline demographics (age, sex, race) or MS characteristics (diagnosis type, EDSS score, disease duration).

Safety and Tolerability

• AEs occurred in 81% of placebo-treated subjects and 91% of f^'ampridine-trcated subjects. Most were mild to moderate in severity and transient.

• The most frequently reported AEs in the fampridine treatment groups were parathesia (10%), insomnia (8%), asthenia (7%), dizziness (7%), and nausea (6%).

• Serious adverse events, judged possibly or likely related to treatment, occurred in 3 subjects

- Fampridine 20 mg bid: two subjects experienced a seizures during the trial, both cases following accidental overdoses (40 mg doses).

- Fampridine 15 mg bid: one subject with altered mental stale following overdose.

Response Analysis

A subset of patients in each tieatment group showed consistently improved walking speed while on drug: 8.5%, 35.3%, 36.0%, and 38.6% of the subjects in the placebo, 10 mg, 15 mg, and 20 mg b.i.d. treatment groups, respectively, as shown in Figure 3.

Figure 3 Percentage of Subjects (ITT Population) with Consistent Improvement in Walking Speed (responders)

Given that there was little difference in responsiveness between the three doses examined, more detailed analyses compared the pooled fampridine-treated groups against the placebo-treated group. These analyses showed that subjects with consistently improved walking speeds averaged a net improvement of >20% in walking speed, during the treatment period and maintained a stable average level of improvement in walking speed at each visit, over the full course of treatment, as shown in Figure 4.

Subjective Correlates of Improved Walking

Among the 205 ITT subjects, 62 experienced consistent improvements in walking speed, based on the posl-lioc definition, while 143 did not Analysis of the clinical meaningfulness of consistent improvements in walking speed indicate that consistency in walking speed improvements had clinical meaningfulness for the subjects in this study since these subjects had significantly better (higher) SGI scores and significantly better changes (reductions) in MSWS-12 perceived disability scoies than those who did not (Figure 5)

Figure 5 Analysis of (he Clinical Meaningfulness υf Consistent Improvements in Walking Speed (Observed Cases, ITT Population)

CONCLUSIONS

These post-hoc analyses showed: • the presence of a larger (x4) subset of subjects who responded to Fampridine-SR with a consistent improvement in walking speed in all fampridine-treated gioups, compaied to the placebo group

• consistent improvement in walking speed was significantly associated with improved Subject Global Impression scores and MSWS-12 scores, indicating that consistent improvement in walking speed on the Timed Walk, associated with this treatment, is clinically meaningful to the subject

These results support the continued investigation of Fampridinc-SR for impiovement of ambulatory function in MS through the prospective identification of a subset of subjects who respond on the Timed Walk test

REFERENCES

1. Blight, A. R. (1989) Effect of 4-aminopyiidine on axonal conduction block in chronic spinal cord injury. Brain Res Bull 22: 47-52.

2. Waxman SG. (1993) Aminopyridines and the treatment of spinal coid injury. J

Neurotrauma 10 19-24

3. Davis, F.A., D. Srefoski, and J. Rush (1990) Orally administered 4-amιnόpyridine improves clinical signs in multiple sclerosis Ann Neurol 27: 186-192.

4. Van Diemen, H A M et al., (1992) The effect of 4-aminopyridine on clinical signs in multiple sclerosis a randomized, placebo-controlled, double-blind, crossover study. Ann Neurol 32: 123-130. 5 Schwid, S. R., et al., (1997) Quantitative assessment of sustained-release 4- aminopyridinc for symptomatic treatment of multiple sclerosis. Neurology 48: 817- 821.

6. McDonald, W I., ct al (2001) Recommended Diagnostic Criteria foi Multiple

Sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis Ann Neurol 50. 121-127

7. Hobart J, Riazi A, Lampling D, Fitzpatrick R, Thompson A (2003) Measuring the

Impact of MS on Walking Ability. J Neurol 60.31-36.

The MS-K202 Fampridinc-SR Study Group:

Barry Arnason, University of Chicago, Chicago, IL

Francois Bethoux, Cleveland Clinic Foundation, Cleveland, OH

Christopher Bever, University of Maiyland at Baltimoie, Baltimore, MD

James Bowen, University of Washington Medical Center, Seattle, WA

Anne Cross, Washington University-Barnes Jewish Hospital, St Louis, MO

Corey Ford, University of New Mexico. Albuquerque, NM

Norman Kachuck, USC School of Medicine, Los Angeles, CA

Michael Kaufman, Caiolinas Medical Center MS Clinic, Charlotte, NC

Lauren Knipp, SUNY Stony Brook, Stony Biook, NY

Thomas Leist, Thomas Jefferson University, Philadelphia, PA

John Lindsey, University of Texas-Houston, Houston, TX

Fred Lublin, Mt Sinai School of Medicine - MS Center, New Yoik, NY

Michelle Mass, Oiegon Health Sciences University — MS Center, Portland, OR Luanne Metz, Foothills Medical Centre, Calgary, ΛB Aaron Miller, Maimonides Medical Center, Brooklyn, NY Paul O'Connor, St. Michael 's Hospital, Toronto, ON Mary Ann Picone, Gimbel MS Center, Teaneck, NJ Kottil Ranimohan, Ohio State University, Columbus, OH Marco Rizzo, Yale New Haven Hospital, New Haven, CT Randall Schapiro, Fairview MS Center, Minneapolis, MN Steven Schwid, University of Rochester, Rochester, NY Craig Smith, Swedish Medical MS Center, Seattle, WA Ben Thrower, MS Center at Shepherd Center, Atlanta, GA

((Fooler bottom left))

Presented at the 130^th Annual Meeting of the American Neurological Association San Diego, California, September 25-28, 2005.

((Footer bottom right))

Dr. Andrew D. Goodman is a consultant to Acorda Therapeutics, Inc. Financial support for this study was provided by Acorda Therapeutics, Inc.

APPENDIX D

RESPONDER ANALYSIS INTRODUCTION

Acoida Therapeutics has sponsored two Phase 2, prospective, randomized, placebo- controlled clinical trials to evaluate the effects of Fampridine-SR on lower extremity motor function in people with multiple sclerosis (MS). Both trials demonstrated statistically significant improvement in leg strength, measured with the standard manual muscle test (LEMMT). Both trials showed improvements in walking speed based on the Timed 25 Foot Walk (TW25) which were statistically significant on the basis of post-hoc analyses. Increasing muscle weakness and ambulatory deficits are two of the most clinically significant aspects of this progressive disease. Fampridine is the first and only drug to date that has shown direct beneficial effects on functional deficits of walking and weakness in MS (as distinct from anti-inflammatory drugs used to promote recovery from acute relapse).

Acorda Therapeutics representatives met with the Division on July 1 , 2004 to discuss the potential for proceeding to Phase 3 studies in light of the results of the most recent trial, MS-F202, a 21 1 patient, dose-comparison study. At this meeting, the Division presented the view that the data from MS-F202 demonstrated only a relatively small and transient effect of the drug on walking speed and that some additional measure of "clinical meariingfulness" of such changes on the TW25 would be required. It was suggested that a subject- or clinician-global measure could provide this role. It was also proposed that this role might be filled by the Multiple Sclerosis Walking Scale- 12 (MSWS-12) a recently developed twelve item questionnaire that addresses walking function, and which was used in an exploratory way in study MS-F202. The Division also made clear the need to demonstrate the maintenance of effect over a 12-week treatment period.

Acorda Therapeutics has taken these recommendations into account and has revised its development plan to address the issues raised by the Division. Acorda now proposes to perform an adequately powered, double blind, randomized, placebo- controlled study to compare the effects of 10 mg b.i.d. Fampridine-SR against placebo on walking in patients with MS. The overall design of this study will be similar to that of study MS-F202, except for the dose comparison aspect of the previous trial, and will include a 14-weck treatment period. As described in the attached protocol synopsis, and with regard to the expressed openness of the Division to considering such an approach, this study will employ a responder analysis as a primary endpoint. This form of analysis will facilitate evaluation of clinical mcaningfulncss of benefit and maintenance of effect in those subjects who respond to the drug. The following will first explain the rationale for the choice of response criterion and then illustrate in detail the application of the proposed analysis by means of a post-hoc analysis of study MS-F202.

The intent of this study and its analysis plan will be to show that there is a significant subset of subjects with ambulatory deficits due to MS who respond to Fampridine-SR with a meaningful increase in walking speed. RATIONALE

Clinicians who regularly prescribe compounded fampridine for MS have reported that only a proportion of their patients appear to respond with clear clinical benefits, and that, in their judgment, this proportion may be around one third (personal communication with Acorda Therapeutics). This extent of responsiveness may be related to the proposed mechanism of action, which is the restoration of conduction in demyelinated axons via the blockade of voltage-dependent potassium channels. Only a proportion of MS patients would be expected to possess axons of appropriate functional relevance that are susceptible to these drug effects, given the highly variable pathology of the disease. Currently, there is insufficient understanding of the disease to allow for pre-trial selection of potentially responsive patients. However, the existence of a subset of patients who respond consistently to the drug can be supported by quantitative observations in studies MS-F201 and MS-F202.

Before treatment, the subjects in these two trials exhibited average walking speeds on the TW25 measure of approximately 2 feet per second (iVsec). This is a significant deficit, since the expected walking speed for an unaffected individual is 5-6 ft/sec. Subjects in MS-F202 were selected for TW-25 walking time at screening of 8-60, which is equivalent to a range in speed of 0.42-3.1 ft/sec. Variability of functional status is an inherent characteristic of MS, and this can be seen in repeated measurement of walking speed over the course of weeks or months. At any of the three visits during the stable treatment period, 15-20% of placebo-treated subjects showed >20% improvement from baseline walking speed, a threshold chosen as one that indicates a true change in walking speed over background fluctuations. A larger proportion of the Fampridine-SR treated subjects showed such improvements, but this difference was not statistically significant, given the sample size and placebo response rate.

Given the often large variations in function experienced by people with MS, it is difficult for the subject or a trained observer to separate a treatment-related improvement from a disease-related improvement without the element of consistency over time. Consistency of benefit might therefore be expected to be a more selective measure of true treatment effect than magnitude of change. Based on this rationale, the responses of the individual subjects in the MS-F202 trial were examined for the degree to which their walking speed showed improvement during the double-blind treatment period and returned towards pre-treatment values after they were taken off drug, at follow-up. This subject-by-subject examination yielded a subgroup of subjects whose pattern of walking speed over time appeared to be consistent with a drug response. This led to the analysis illustrated in Figure J . This coinpaics the placebo and Fampridine-SR treated groups with respect to the number of visits during the double-blind treatment period in which walking speed on the TVV25 was faster than the maximum speed out of all five of the non-treatment visits (four visits prior to randomization and one follow-up visit after the drug treatment period).

The placebo-treated group showed a clear pattern of exponential decline in numbers of subjects with higher numbers of "positive" visits. This is what would be expected from a random process of variability (a simple computer simulation of the random sampling process involved shows the same pattern of response - Fig. Al in the Supplemental Tables and Figures). In contrast, the pattern of response in the Fampridine-SR treated group strongly diverged from this distribution; much larger numbers of Fampridine-SR treated subjects showed three or four visits with higher walking speeds than the maximum speed of all five iion-trcalmcnt visits and less than half of the expected proportion had no visits with higher speeds. These results indicate that there was a sub-population of subjects in the Fampridine-SR treated group that experienced a consistent increase in walking speed related to treatment.

This analysis suggests that a lelatively highly selective criterion for a likely treatment responder would be: a subject with a faster walking speed for at least three (i.e., three or four) of the four visits during the double blind treatment period compared to the maximum value for all five of the non-treatment visits. The four visits before initiation of double-blind treatment provide an initial baseline against which to measure the consistency of response during the four treatment visits. The inclusion of the follow-up visit as an additional component of the comparison was found valuable primarily in excluding those subjects who did not show the expected loss of improvement after coming off the drug. These are likely to be subjects who happened by chance to have improved in their MS symptoms around the time of treatment initiation, but whose improvement did not reverse on drug discontinuation because it was actually unrelated to drug. Thus, incorporating the follow-up visit as part of the criterion may help to exclude false positives, if the TW25 speed remains high at follow-up.

In study MS-F202, this responder criterion was met by 8.5%, 35.3%, 36.0%, and 38.6% of the subjects in the placebo, 10 mg, 15 rag. and 20 mg b.i.d. treatment groups, respectively, showing a highly significant and consistent difference between placebo and drug treatment groups. Given that there was littic di fference in responsiveness between (he three doses examined, more detailed analyses were performed comparing the pooled Fainpridine-SR treated groups against the placebo- treated group The full results of this analysis for study MS-F202 are described in the following sections. These show that the rcsponder group so identified experienced a >25% average increase in walking speed over the treatment period and that this increase did not diminish across the treatment period. The responder group also showed an increase in Subject Global Impression score and an improvement in score on the MSWS- 12. If this same pattern of improvement on the secondary endpoints is confirmed in the prospectively designed studies, the clinical meaningfulness of the response definition will be supported.

It is important to note that this responder criterion selects subjects who show a pattern of change that is consistent with a treatment response, but does not define the full characteristics of that response. The criterion itself does not specify the amount of improvement nor does it specify that the improvement must be stable over time. For example, a progressive decline in effect during the course of the study period, even one resulting in speeds slower than the maximum non-treatment value, would not be excluded by the criterion; as a specific example, changes from the maximum non- treatment value of, respectively, +20%, +5%, + 1 % and -30% during the double blind treatment period would qualify as a response under the criterion, but would actually show a net negative average change for the entire period, poor stability and a negative endpoint. Post-hoc analyses of studies MS-F202 and MS-F201 indicate that we may expect responders defined by consistency of effect also to demonstrate increased magnitude and stability of benefit, but this must be determined in a well-controlled trial in which this responder criterion is pre-defined.

RESPON DER ANALYSIS APPLI ED TO STUDY MS-F202

Given that tlierc was little difference in icspoiisiveness between the thiee drug doses examined in Stud)' MS-F202 (see Table Al in the Supplemental Tables and Figuies) the following analysis primarily compares the pooled Fampridine-SR treated groups against the placebo-treated group

The number of sub|ects who met the responder ci iterion in the pooled Fampridine-SR treated group was 58 (36 7%) compared to 4 (8 5%) in the placebo-treated group, and this difference was statistically significant (p<0 001 ) as shown in Table 1 Fig A2 (see Supplemental Tables and Figures) illustiatcs the mean changes walking speeds by visit for these two groups

This indicates that the chances of a mote favoi able outcome, based on consistency of improvement in walking speed, is much higher in the Fampridine-SR treated than in the placebo-treated gioup

Figure 2 compares changes in walking speed foi the Responder and Non-Responder groups between the Fampndine-SR and placebo-treated groups The Fampridine-SR Responder group showed an average increase in speed of 0 49 ft/sec compared to 0 01 ft/sec in the two Non-Responder groups The foui Placebo Responder subjects showed an intermediate average change in walking speed (0 33 ft/sec) but there were too few subjects in this group for meaningful comparison There was no difference between the groups at baseline in baseline walking speed, demographics, or neurological chaiacter istics (see Table A2, A3, and A4 in the Supplemental Tables and Figures)

S<->

The average percent improvement from baseline in walking speed during the double blind period was 27% for the Fampridine-SR Responder groups, compared to 1 and 2% in the Placebo and Fampridine-SR Non-Responders, respectively, as shown in Figure 3.

Fig. 3 Average percent change in walking speed during the double-blind treatment period, compared to average pre-randomizalion value, by responder classification.

Not only was the magnitude of effect on average walking speed substantial in the Fampridine-SR Responder group, but the effect was stable and the confidence intervals well separated from the non-responder groups over the full 14-week treatment period, as shown in Figure R.

Fig. 4 Percent change in walking speed, compared to average pre-randomization values, by responder classification at each study visit during the double-blind treatment period. For clarity, the upper graph shows only the Fampridine-SR Responder group and the Fampridine-SR and Placebo Non-Responders The lower graph includes the Placebo Responders, showing the large confidence intervals which would otherwise obscure the display of confidence intervals foi the other groups The response criterion also allows us to explore the beneficial defects of this change as reported by the subjects on two global mcasui cs, the Subject Global Impression (SGl) and Multiple Sclerosis Waling Scale- 12 (MSWS- 12), as illustrated in Figures 5 and 6, below. The Responders showed a higher average score on the SGI during the double-blind treatment period. These SGI data indicate that Responders were able to distinguish a positive benefit associated with their improvement in walking speed. A larger sample would be required to confirm this difference statistically given the highly variable nature of responses on these variables (see Fig. A3 and A4 in the Supplemental Tables and Figures).

Fig. 5 Average Subject Global Impression score by responder classification during the double- blind treatment period A score of 4 is a response of "neutral/miλed" on a 7-point 1errιble(l ) to Delighted (7) scale

Clinical mcaningfulness of the responder criterion is also supported by the fact that Responders showed greater improvement on the MSWS- 12 questionnaire, as shown in Figure 6. below. Note that the MSWS- 12 was only applied at Visit 0 (before placebo run-in) and at the first and last stable dose visits in study MS-F202

Fig 6 Average change from baseline (Visil 0) in MSWS- 12 score during (he double-blind treatment period, by responder classification The MSWS-12 scoie has a maximum value of 100 for the most severe impact of MS upon ambulatory function in daily life functions

In summary, this responder analysis illuminates chaiacteristics of the response that are not clear from analysis of the whole treatment population. The benefit on walking in Responders appears to be both substantial, with an average improvement of more than 25%, and quantitatively consistent over the 3-month period of the treatment In addition, the Responders appear to iegister then impressions of clinical benefit on both the SGI and MSWS-12.

PROPOSAL FOR NEXT PHASE 2 STUDY

With the benefit of these analyses applied retrospectively to study MS-F202 and also to study MS-F201 (see Table A5 in the Supplemental Tables and Figures) Acorda Therapeutics proposes to perform a new prospective study, based closely on the design of MS-F202. A dose of 10 mg b.i.d. has been chosen since there was little evidence of a dose-related increase in response. Therefore, the lowest dose has been chosen in order to minimize adverse events, including, hopefully, the risk of seizures.

As described in the attached protocol synopsis, this study will declare a primary endpoint of response on the pre-defined responder analysis. In addition, as part of the secondary analyses, the clinical meaningfυlness of these improvements will be assessed by the magnitude of improvement in speed on the TVV-25 and with the SGl and MSWS-12 global instruments. Further clinical benefit will be assessed by use of the LEMMT to measure lower extremity muscle strength.

This new study is expected to demonstrate significance on the responder analysis, based on consistency of response over time. It is also expected to demonstrate sustained increase in walking speed in Responders compared to Non-Responders. The study may also demonstrate improvement in Responders on the global measures (SGI and MSWS- 12). In the event that the study is not able to demonstrate clear separation of Responders on these global measures, it is expected to provide additional information on variability and sensitivity of the instruments to changes in walking speed. This will be useful in further assessing the potential validity of these measures in this context and may permit appropriate power calculations for subsequent studies.

SUPPLEMENTAL TABLES AND FIGURES Rcsponder Rate for Individual Dose Groups (MS-F202)

The response rate of Fanipricline-SR treated subjects seen in the pooled analysis was consistent within the three drug groups, as shown in Table Al Likewise, individual dose group analyses of magnitude of effect, maintenance of effect and linked global effects are broadly consistent, though the small sample sizes limit the significance of the observed effects.

Baseline Characteristics of Responder Groups (MS-F202)

There were no significant differences between Responder, Non-responder and Placebo groups in terms of baseline characteristics or demographics, as shown in the following tables (A2-A4).

Equivalent Responder Analysis in Study MS-F201

In this analysis, data from Study MS-F201 was tieated in an approximately equivalent manner to the approach foi MS-F2O2, using the first four visits on drug (one visit per week, with weekly dose escalation through 10, 15, 20 and 25 nig b i d.) and comparing to 5 visits "off drug" before randomization. This was a smaller study, with a very small placebo group, but the results of the responder analysis were largely consistent with Study MS-F202, particularly with regard to the percent frequency of response in the Fampridinc-SR and placebo-treated groups The MSWS- 12 measure was not used in this study.

Probability of Treatment Visits with Faster Walking Speed (MS-F202)

Fig. Al Histogram to compare the observed frequency of faster walking speed during treatment visits in the placebo group (as shown in figure 1) compared with a computer model simulation of the underlying sampling procedure The simulation involved computer generation of 100,000 trains of 9 random numbers and testing the frequency with which numbers 5-8 were larger than the maximum of the numbers 1-4 and 9 in each tram The model predicts an exponential decline in probability of larger numbers of positive visits, and the observed values were close to this distribution The slightly higher observed values may relate to the trend for increase in mean walking speed over the course of the trial in the placebo group (see Fig. A2)

Change in Walking Speed Over Time of Treatment - Fooled Fanipridine-SR

Group (MS-F202)

Fig. Λ2 Plot and table to compare the average change in walking speed at each treatment visit for the pooled Fampridine-SR group with the change in the Placebo group Changes in this original analysis were measured from the average during the placebo run-in visits This analysis gives the impression of an initial improvement in speed which declines over time, losing significance by the last study visit The respondcr analysis (as in Fig. 4, above) shows that the apparent decline in improvement was actually due to an early transient improvement and a subsequent drop on the last visit in the Fanipndine-SR Non-Responder group The Fampridine-SR Responder subjects, with a consistent improvement throughout treatment were responsible for the great majority of the overall treatment effect Hence the temporal variability seen here in the analysis of means appears to be quite separate from the marked treatment-related improvement in speed Note that any subjects who actually showed d pattern of response similar to the Fampridine-SR group mean would almost certainlv meet the responder criterion and would be included in the Responder categoiy

Variability of Global Measures (MS-F202)

The data from study MS-F202 provide only limited information on the two subject global measure (SGI and MSWS-12) but sufficient to illustrate the highly variable nature of responses on these instrument. Even in the placebo-treated group, both SGI and MSWS-12 showed a much higher range of spontaneous variability between study visits than the TW25 or lower extremity strength, which are more direct and objective measures of function (see Figure A3 below)

Fig. A3 Scatterplots showing the variability of foui different measures of lower extremity function between baseline measurements and measurements alter 6 weeks on double-blind study (Study Day 56) for the Placebo-treated group in Study MS-F202 Both the SGI and the MSWS- 12 show more variability (spread) and less overall stability (slope) with respect to baseline than the walking speed on the TW25 and leg strength on the LEMMT scale Note that the SGI is restricted to integer values, and the plot indicates the iange of values and the frequency by number at points with frequency > 1

Further analysis of the MSWS-12 scores in placebo-treated subjects, is provided in Figure A4 This shows that the individual's assessment of the impact of ambulatory deficits on everyday function is remaikably variable for a given level of objective deficit, as defined by the tuned walk This is likely to be leflective of wide dispai ities in subject expectation and adopted lifestyles, which can allow one subject to feel severely disabled by a lelatively small decline in motor function while another may adapt lifestyle and expectation to a persistent, severe ambulatory deficit, and might therefore take some considerable time to re-adapt to or even recognize a new level of function

Fig A4 Scatterplol to show the relationship between the MSWS- 12 score and walking speed, measured with the TW25 for the entire placebo treated group over nil four study visits at which the instrument was used The MSWS- 12 score shows increasing severity of impact on walking speed with higher numbers A normal walking speed is 5 5 6 ft/sec

APPENDIX F

The Range Disparity Distribution and Its Applications

Lawrence N. Marinucci¹, Tai Xie², Ron Cohen¹, Andrew R. Blight¹

¹Acorda Therapeutics Inc , 15 Skyline Drive, Hawthorne, New York, 10532

^rightech International, Two Worlds Fair Dr , Suite 101, Somerset, New Jersey, 08873

Keywords: probability distribution, central treatment arm who had tumor burden tendency range, sample distributions, reductions greater than the largest reduction in exceptional values the standard therapy arm For this situation, the range of the efficacy measure may provide

Abstract more relevant evidence of treatment effect

Conventionally inferential statistics focus on than the population mean particularly in measures of central tendency, e.g the situations were a majority of those treated do population mean and variance Little attention not respond is given to the range of sample distributions, while the range is often associated with With few exceptions, such as Lord's Range exceptional values Under certain Test and others ^2,3,4, little attention is given to circumstances, effects visible at the ranges ot a the range of sample distributions, while the sample may provide more sensitive and even range is often associated with exceptional more meaningful measures of differences values This situation, in a different clinical between populations than the differences in context, led us to think about how to formulate means In this paper we intioduce a a piactical statistical test for the range of a distribution of "range disparity" to describe the distribution probability that a given number of items in one set fall outside the range of all the items in 2. The Range Disparity Distribution another set on a given measure It can be used To illustrate the idea, we suppose that there are to form statistical inferences from the range three urns, call them X, Y and ZL Suppose differences of two independent samples, urn Z contains 10 straws of slightly different irrespective of the underlying population lengths. A referee selects five straws, places distribution. We will also provide several them into urn X and places the remaining live practical application examples straws into urn Y What is the probability distribution that a gi\ en number of straws in

1. Introduction urn Y arc longer than the longest straw in um

Li a controlled clinical trial, testing a new drug X? versus atlixe control or placebo, the main • The probability is 5 out of 10 for urn X to objectives mav, locus on assessing treatment pro"ide the longest straw Similarly, there eflect in reducing symptoms or conditions at is a 5/10 chance that uπi Y will have no baseline For example in refractory oncology straws longer than the longest straw in urn studies patients aie randomized into either a X standard therapy or a new experimental • For urn Y to have exactly one straw therapy The tumor response, defined as at longer than the longest straw in urn X least 25% reduction from baseline in the sum o urn Y must fiist have the longest ol the bi-dimensional longest diameters lor straw (a 5/10 chance; target lesions¹ (the ' tumor burden ) is o one ol the ti\c straws in urn X must commonly used as a primary endpoint Io be the longest among the remaining obtain accelerated iegulatory approval In a nine straws ia 5/9 chance). relectory study. the patient lias prewously So the piobαbility for urn Y to have failed to respond to the standard therapv (i e exactly one stiav\ longer than the longest at tills point, it would be assumed impossible straw in urn X is 5/10 X 5/9 foi a 100% i eduction in the standard therapy • For uπi Y Io have e\αctly two straws arm) Frequently there are no overall group longer than the longes straw in uin X, urn dillereπces in the average lcspoibc, but there Y must lirst have is an obv ious advantage in the tail of the o the longest straw overall (a 5/10 distribution ol the tumor burden. For example, chance) there may be a number of subjects in the

absence of treatment effects as being approximately 1.79%, independent of any experience with actual data. From the Range Disparity Distribution, it is possible to select a priori a number of measurements and a criterion for response that sets a desired frequency of expected false positive response. This is only possible in more conventional

forms of response analysis by reference to whicli completes the proof. Via (2), the historical data on expected rates in untreated expected value and variance of the RDD can or placebo-treated populations. be shown to be and Example 3.2: The application of this

distribution is particularly powerful in the context of a repeated measures response

, respectively. The proofs analysis of the kind provided by example in

3.1 above. However, it may be useful in for the mean and variance will be presented in simpler situations, for example, in a case of a forthcoming paper. industrial product sampling. There might be a suspicion that plant A is producing items with a breaking strength that is lower than those

3. Examples from plant B. A limited sample of destructive

Example 3.1: Suppose we have a clinical trial testing of items from the two plants may be such that for each subject, we have S off- available. If it has been determined that in a treatment measurements and T on-treatment sample of 5 items from each plant the breaking measurements for a particular outcome strength of more than 2 of the ilems from plant variable. If we define a random variable Y as A falls below the range of the 5 tested from the number of on-treatment measurements that plant B we would have support for the are better than the best off-treatment suspicion regarding a difference between the measurement, then based on the RDD we plants. More specifically, we would know that could compute the probability distribution of there is less than a 2.5% chance, on the basis Y. Specifically, if for each subject there were of random variability, that 4 or 5 of the 5 off-treatment measurements and 3-on- samples from A would fall below the failure treatment measurements, we know from the range for those from plant B. RDD that we would expect approximately 4. Conclusions 62.5% of the patients to have no on-treatment measurements that are better than the best off- The Range Disparity Distribution provides a Ireatirient measurement. 26.8% to have one basis for statistical testing of difference in the on-treatment measurement that is better than upper or lower range of two samples. This is the best off-treatment measurement and so particularly useful in designing clinical forth; under the assumption of no treatment experiments for detecting and measuring effect and that there is no longitudinal effect responses occurring only in a subset of a on the outcome measure. That is to say that, sample population. This approach can be over time, there is at best, negligible within- expected to find much broader application and subject correlation. to direct more attention to the information contained in the often neglected data that

Departures from these assumptions will exists beyond the range. become, apparent in the analysis itself. As a practical example, the probability that all three 5. References on-treatment measurements are better is (11 Therasse, P., et. al., New Guidelines to 1.79%. Therefore a criterion for treatment Evaluate the Response to Treatment in Solid response can he established, defined as all Tumors, J Nat Cane List, 2000;92(3):205-216 tlircc on-trcatmcnt measurements being better (2) Lord, E 11947) The use of range in place than the best off-treatment measurement for an of standard deviation in the 1-Test. individual patient. The advantage of such a Bioinetrika 34: 41-67. criterion for response is that it is possible to predict the frequency of response in the (3) Moore, PG (1957) The two-sample t-tcst based on range. Biometrika 44: 482-489.

(4) Irwin JO (1925) On a criterion for the rejection of outlying observations. Biometrika 17: 238-250.

Claims

WE CLAIM:

1. A method for selecting individuals based on responsiveness to a treatment, the method comprising the following steps: identifying a plurality of records relating to patients in a clinical database, said records comprising measurements for patients relating to tests administered during an off-treatment period and an on-treatment period; identifying at least one test in said plurality of records relating to measurements of each individual during an off-treatment period; identifying at least one test in said plurality of records relating to measurements of each individual during an on-treatment period; identifying a baseline measurement of each individual during said off-treatment period; performing a statistical distribution on said plurality of records to identify likelihood of said on-treatment and said off-treatment measurements exceeding said baseline so as to compare said measurements with said baseline; and selecting one or more individuals, wherein the selected individuals exhibit an improved performance during a majority of the tests administered during the on-treatment period as compared to a best response to said at least one test administered to the off-treatment period.

2. A computer program product, for use with a computer system, for selecting individuals based on responsiveness to. a treatment, the computer program product comprising: a computer readable medium containing thereon instructions operative to control the operation of a computer system to perform the steps of: identifying a plurality of records relating to patients in a clinical database, said records comprising measurements for patients relating to tests administered during an off-treatment period and an on-treatment period; identifying at least one test in said plurality of records relating to measurements of each individual during an off-treatment period; identifying at least one test in said plurality of records relating to measurements of each individual during an oπ-treatmeπl period; identifying a baseline measurement of each individual during said off-treatment period; performing a statistical distribution on said plurality of records to identify likelihood of said on-treatment and said off-treatment measurements exceeding said baseline so as to compare said measurements with said baseline; and selecting one or more individuals, wherein the selected individuals exhibit an improved performance during a majority of the tests administered during the on-treatment period as compared to a best response to said at least one test administered to the off-treatment period.

3. A computer based system for selecting individuals based on responsiveness to a treatment said system comprising: a memory module for storing patient measurements, and for storing at least a first set of instructions relating to the inputting and analyzing of said patient measurements, and a second set of instructions for outputting responder information from said patient measurements; a central processing unit for executing said first and second set of instructions, and for outputting the responder information resulting from said executing of said first and second instructions, said central processing unit being connected to said memory module, and in operative control of said memory module; and an output module connected to said central processing unit for displaying said responder information.

4. The method of claim 1, further comprising the step of analyzing subjects and validating a clinical meaningfulness of a post hoc responder variable by comparing a group of iesponders against a group of non-responders based upon subjective variables to determine if any of said subjects who exhibited improved response during a double blind could perceive benefit lelative to any subjects who had not exhibited impioved i espouse during said double blind

5 The method of claim 4, further comprising the step of establishing said baseline by establishing a baseline comparability among groups of said subjects who exhibited improved response by analyzing baseline demographic variables, key neurological characteristics, and relative efficacy variables at said baseline

6. The computer program product of claim 2, for use with a computer system, for selecting individuals based on responsiveness to a treatment, the computer program product comprising: a computer readable medium containing thereon further instructions operative to control the operation of a computer system to perform the additional steps of: analyzing subjects and validating a clinical meaningfulness of a post hoc responder variable by comparing a group of responders against a group of non-responders based upon subjective variables to determine if any of said subjects who exhibited improved response during a double blind could perceive benefit relative to any subjects who had not exhibited improved response during said double blind.

7. The computer program product of claim 6, for use with a computer system, for selecting individuals based on responsiveness to a treatment, wherein the instructions contained by said computer readable medium included with said computer program product further comprise: establishing said baseline by establishing a baseline comparability among groups of said subjects who exhibited improved response by analyzing baseline demographic variables, key neurological characteristics, and relative efficacy variables at said baseline.

8. The computer based system for selecting individuals based on responsiveness to a treatment of claim 3, said central processing unit further comprising: means for analyzing subjects and validating a clinical meaningfulness of a post hoc responder variable by comparing a group of responders against a group of non-responders based upon subjective variables to determine if any of said subjects who exhibited improved response during a double blind could perceive benefit relative to any subjects who had not exhibited improved response during said double blind.

9. The computer based system for selecting individuals based on responsiveness to a treatment of claim 3, said central processing unit further comprising: means for establishing a baseline comparability among groups of said subjects who exhibited improved response by analyzing baseline demographic variables, key neurological characteristics, and relative efficacy variables at said baseline.