Multiple Sclerosis Research Repository

From FDA Application Number: 761053Orig1s000 Summary Review: Ocrevus

-The review team is in partial agreement (as noted, Dr. Marler dissents) that the applicant has provided substantial evidence of effectiveness for the use of OCR for the treatment of patients with primary progressive multiple sclerosis. This conclusion is primarily supported by evidence

from a single study in PPMS (Study WA25046) that evaluated the use of a single dosing regimen of OCR, with additional support from results of the RMS studies described above. This PPMS study evaluated a primary outcome of time to confirmed disability progression, comparing OCR to placebo.

-Despite concerns regarding an unusual imputation of confirmed disability progression in the absence of an actual measurement (i.e., patients that had an initial event of disability progression but left the study before progression could be confirmed at a second visit 12 weeks later were imputed as confirmed disability progression endpoints), a sensitivity analysis performed by Dr. Yan based on assignment of the imputed endpoints to an event status (i.e., contributing to the count of confirmed disability progression or being censored at the time of withdrawal) based on the actual proportion of confirmed disability progression events in patients that had an initial event of disability progression observed in the study was supportive of primary outcome. Also, a reduction in the occurrence of relapse favoring OCR was seen in

the PPMS study. The members of the review team are not unanimous with regard to the evidence that the PPMS study provides, as I noted above. Dr. Yan and Dr. Rodichok support approval for PPMS, while Dr. Marler argues against it. Dr. Marler expresses concern not only about the strength of the PPMS study, but he also doubts the ability of the RMS studies (which showed an effect on disability progression in RMS) to support the PPMS study, leading him to conclude that the PPMS study must be considered on its own. Dr. Rodichok shares concerns about the ability of the RMS studies to support the PPMS study, but recommends approval based on the results of the PPMS study and the unmet medical need in this area.

-Whether the RMS studies may serve to support the PPMS study deserves some comment in light of the extensive assertions of Dr. Marler and Dr. Rodichok that they cannot.

-Although Dr. Rodichok and Dr. Marler argue otherwise, I think it is clear that the results of the RMS studies are relevant to the findings of the PPMS study. RMS is clearly related to PPMS, as both are forms of a single disease, multiple sclerosis. That there are differences between these

two forms of MS is not in doubt. If differences could not exist at all, then they would not be different forms and the RMS studies would suffice without any PPMS study. Differences, however, do not preclude the ability of the RMS studies to support the PPMS study. Dr. Rodichok and Dr. Marler argue that differences in the PPMS and RMS populations in demographic and baseline disease characteristics, along with differences in the characteristics of the periods of disability in those populations, is indicative of a lack of relatedness that precludes the ability of one to support the other. This argument is based primarily on assertions that outcome events of interest should have an empiric sameness in order to be related and that the differences in these various characteristics is indicative of differing pathophysiological mechanisms.

-It is important to recognize that arguments related to “relatedness” are inherently subjective. Although many individual points are made by Dr.Rodichok and Dr. Marler in an attempt to support the position that the two forms of MS are not related, such an overall position is not suited for point by point refutation, lest one inadvertently establish some type of semi-quantifiable threshold beyond which relatedness is present. Suffice it to say, our considerations of this issue (made pre-submission, not unimportantly) have resulted in our position that these forms of MS are related, and may serve to support each other. Indeed, it might appear almost self-evident that, by definition, they are both MS. It is true that our thinking

in the Division regarding the degree of relatedness has evolved from advice given previously that suggested that a conventional independent development program for PPMS was required. Previous advice was based on our perception of the understanding of the scientific community

and our own understanding concerning the independence of the pathophysiological mechanisms underlying the forms of MS. We have evolved our thinking from our previous position, consistent with a contemporary understanding of MS. Our judgment is that these forms of MS are related, and the Division is prepared to accept PPMS and RMS populations as mutually supportive.

-Although much literature may be cited that notes a variety of pathophysiological distinctions based on any number of research avenues, the phenotypic categorization of MS into PPMS and other forms (including RMS), a categorization that is the fundamental issue at play, was the

result of definitions put forth in 1996 by the US National Multiple Sclerosis Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis. The distinction was not made on the basis of a fundamental, well-established, and well-understood scientific characterization of the

pathophysiology of the various forms of MS. At the time they were proposed, that committee noted that these phenotypic descriptors were consensus subjective views of experts in the field and were not supported by objective biological findings. That same committee recommended

that the phenotypic descriptors (MS subtypes) should be re-addressed as the scientific understanding of the disease evolved. In that spirit, The International Advisory Committee on Clinical Trials in Multiple Sclerosis (now a jointly sponsored international entity of the NMSS and The European Committee for Treatment and Research in MS) began in 2011 to explore advances in this area and convened in 2012 to formally review the 1996 classification. This review resulted in the publication in 2013 of revisions to the 1996 definitions. Clearly articulated in these revisions is the notion that PPMS is related in a fundamental pathophysiological manner to other forms of MS. While many aspects of the revisions relate to the relatedness of MS subtypes, the following quote speaks directly to the issue: “While some evidence suggests that PPMS represents a distinct, noninflammatory or at least less inflammatory pathologic form of MS, abundant clinical, imaging, and genetic data suggest that PPMS is a part of the spectrum of progressive MS phenotypes and that any differences are relative rather than absolute. Analyses of natural history cohorts demonstrate that worsening proceeds at a similar rate in SPMS and PPMS. PPMS should remain a separate clinical course because of the absence of exacerbations prior to clinical progression, but it likely does not have pathophysiologically distinct features from relapsing forms of MS that have entered a progressive course (SPMS).” (Lublin, Fred D., et al. Defining the Clinical Course of Multiple

Sclerosis: The 2013 Revisions. Neurology. 2014 Jul 15; 83(3): 278-86.) It is true, of course, that the emphasis of this statement is on the progressive course of the various subtypes, but it illustrates the fact that there is substantial overlap of the subtypes with regard to clinical

subtypes and likely pathophysiology, and that there is a reasonable basis to believe that demonstrated benefit in one subtype may increase the expected reliability of a finding of benefit in a study of a related subtype.

-An additional comment is needed on the notion of considering this issue of the acceptability of “relatedness” during the review of the application. The Division clearly stated in pre-submission discussions with the sponsor that it was acceptable in principle to support the single PPMS study with the RMS studies (recognizing that the adequacy of the data was, of course, a matter for review, as it is for all applications) and reiterated that statement de facto by filing the application. In fact, the Division, in an effort to ensure streamlined and efficient review, particularly in light of the reported results in PPMS, actively advised the sponsor to submit the PPMS study and RMS studies in a single application, contrary to the sponsor’s initial plans to submit the data in two independent applications. Indeed, if the RMS studies were not suitable for support of the PPMS study (i.e., because they were not sufficiently related) then the sponsor should have been (and would have been) advised to conduct another study in PPMS. To delay the conduct of such an additional study in this area by accepting for review an application that could not, on face, be approved because the supportive data are in character fundamentally unacceptable would be deeply troubling. This issue of the “relatedness” of PPMS and RMS is not a typical “matter for review” to be adjudicated during the review process but is primarily a policy “matter for review” that largely took place pre-submission. The Division’s comments to the sponsor were clear in this regard,and the Division is cognizant of the problematic issues that would be raised by “moving the goalposts” after accepting the application.

-With questions of “relatedness” resolved, the persuasiveness of the PPMS study is the remaining issue. In this regard, the primary clinical review and CDTL review do not take into account the additional sensitivity analysis performed by Dr. Yan that is described above. It is certainly true that the unusual approach to imputation was a significant concern and that eliminating all the imputed data severely weakened the primary result, but we were able to use the data within the study itself to inform a more reasonable approach to the consideration of the patients for whom confirmation of an initial disability progression was not available. That approach indicated that the statistical significance of the primary outcome was a valid representation of the effect of OCR in the PPMS study. This result, supplemented by unequivocal and very strong findings in the RMS studies, is strongly supportive of the effectiveness of OCR for PPMS. Further support is provided by effects on relapse, walking speed, and MRI findings in the PPMS study itself. Taken together, these various results provide substantial evidence of effectiveness for the use of OCR in PPMS. It is worth making a brief comment on the previous “failures” in PPMS. Dr. Rodichok and Dr. Marler point out the lack of positive outcomes in trials of other agents in PPMS. Many of those descriptions of failure, however, are simple dichotomous characterizations based on p>0.05. Actual clinical findings numerically favored drug in those trials, in general, particularly in the larger trials, and MRI results trended similarly. This relatively consistent trend can be nothing more than hypothesis-generating, of course, whether for any individual drug or for the group of studied drugs as a whole, but it is intriguing. These clinical findings in previous studies concerned various measurements of disability, a notoriously difficult endpoint on which to achieve success. Disability events in MS are more complicated and difficult to study than simple counts of relapse; they occur remarkably infrequently and studies are often underpowered for this outcome. Pooling of sister trials is often necessary to achieve the power to demonstrate statistical significance for disability. Indeed, this was the prespecified plan for the RMS studies of OCR, anticipating an inability to demonstrate a beneficial effect in the individual trials. Despite this expectation, in addition to winning on this planned pooled analysis, OCR actually won in both individual RMS trials. This further reinforces the belief that the disability finding in PPMS is credible. Though purely speculative, it may be that we have hints that drugs effective in RMS may not be as ineffective in PPMS as generally thought, and that the totality of what we see with OCR may suggest that it is actually remarkably effective on disability across clinical phenotypes of MS. The previous apparent inability of other RMS drugs to affect disability in PPMS is undoubtedly noteworthy, but there may have been less failure than meets the eye and only further clinical studies will be able to address the issues involved. Past experience is certainly a reasonable basis for concluding that effectiveness in RMS should not be extrapolated to PPMS and that independent evaluation in PPMS is needed, but the failure of other drugs, often of dissimilar character, is not a basis for rejecting a clear benefit seen in such an independent evaluation. Subgroup analyses by gender warrant mention. An apparently flat effect on disability in women in the PPMS study is noteworthy (though, it must be kept in mind, such subset analyses are exploratory and not necessarily indicative of an absence of actual benefit on disability in this subgroup). Morevover, somewhat reassuringly (again, keeping well in mind the exploratory nature of such analyses), there are effects on relapse and MRI findings in those same women and there is no gender imbalance for the benefits seen in the RMS studies. Reference ID: 4076435 Division Director Review Page 31 of 32 Although of limited interpretability, we will describe these findings in labeling to more fully inform both prescriber and patient. 

-Given the presence of substantial evidence of effectiveness and the acceptable safety profile, the risk benefit profile of OCR is favorable and supports approval. RMS is a serious and life-threatening condition, and we know that, given individual patient variability, continued development and approval of drugs for RMS is important. There are no treatments for PPMS, also a serious and life-threatening condition and one in dire need of an approved therapy. The biological activity of OCR is presumed to be mediated through a mechanism not shared with other approved drugs for MS. 

-With questions of “relatedness” resolved, the persuasiveness of the PPMS study is the remaining issue. In this regard, the primary clinical review and CDTL review do not take into account the additional sensitivity analysis performed by Dr. Yan that is described above. It is certainly true that the unusual approach to imputation was a significant concern and that eliminating all the imputed data severely weakened the primary result,but we were able to use the data within the study itself to inform a more reasonable approach to the consideration of the patients for whom confirmation of an initial disability progression was not available. That approach indicated that the statistical significance of the primary outcome was a valid representation of the effect of OCR in the PPMS study. This result, supplemented by unequivocal and very strong findings in the RMS studies, is strongly supportive of the effectiveness of OCR for PPMS. Further support is provided by effects on relapse, walking speed, and MRI findings in the PPMS study itself. Taken together, these various results provide substantial evidence of effectiveness for the use of OCR in PPMS.

-It is worth making a brief comment on the previous “failures” in PPMS. Dr. Rodichok and Dr. Marler point out the lack of positive outcomes in trials of other agents in PPMS. Many of those descriptions of failure, however, are simple dichotomous characterizations based on p>0.05.

Actual clinical findings numerically favored drug in those trials, in general, particularly in the larger trials, and MRI results trended similarly.This relatively consistent trend can be nothing more than hypothesis-generating, of course, whether for any individual drug or for the group of

studied drugs as a whole, but it is intriguing. These clinical findings in previous studies concerned various measurements of disability, a notoriously difficult endpoint on which to achieve success. Disability events in MS are more complicated and difficult to study than simple

counts of relapse; they occur remarkably infrequently and studies are often underpowered for this outcome. Pooling of sister trials is often necessary to achieve the power to demonstrate statistical significance for disability. Indeed, this was the prespecified plan for the RMS studies of

OCR, anticipating an inability to demonstrate a beneficial effect in the individual trials. Despite this expectation, in addition to winning on this planned pooled analysis, OCR actually won in both individual RMS trials. This further reinforces the belief that the disability finding in PPMS is

credible. Though purely speculative, it may be that we have hints that drugs effective in RMS may not be as ineffective in PPMS as generally thought, and that the totality of what we see with OCR may suggest that it is actually remarkably effective on disability across clinical

phenotypes of MS. The previous apparent inability of other RMS drugs to affect disability in PPMS is undoubtedly noteworthy, but there may have been less failure than meets the eye and only further clinical studies will be able to address the issues involved. Past experience is certainly a reasonable basis for concluding that effectiveness in RMS should not be extrapolated to PPMS and that independent evaluation in PPMS is needed, but the failure of other drugs, often of dissimilar character, is not a basis for rejecting a clear benefit seen in such an independent evaluation.

-Subgroup analyses by gender warrant mention. An apparently flat effect on disability in women in the PPMS study is noteworthy (though, it must be kept in mind, such subset analyses are exploratory and not necessarily indicative of an absence of actual benefit on disability in this

subgroup). Morevover, somewhat reassuringly (again, keeping well in mind the exploratory nature of such analyses), there are effects on relapse and MRI findings in those same women and there is no gender imbalance for the benefits seen in the RMS studies. Although of limited

interpretability, we will describe these findings in labeling to more fully inform both prescriber and patient.

-The evidence for an effect on disability is sufficient for PPMS.  It is supported by the RMS results and by similar effects on relapse in PPMS.  The effect on disability and other aspects of the disease for PPMS is sufficiently persuasive and addresses an important unmet need

-in WA21092 trial (RRMS): 24-week CDP: OCR 600mg: 0.0278 

-in WA21093 trial (RRMS): 24 week CDP: OCR 600mg: 0.0370 

-in WA21092 (RRMS): 24-week CDP pooled: OCR 600mg: 0.0025 (pooled with WA21093)

-In WA21093 (RRMS): 24 week CDP pooled: OCR 600mg: 0.0025 (pooled with WA211092)

-There was a significant reduction in 12-week CDP in the OCR group.

-With regard the related endpoints of CDP lasting 12 and 24 weeks, the primary and first secondary outcomes of the trial, the protocol-defined primary analysis allowed initial onset of disability progression for patients who withdrew from the study to be imputed as confirmed without actual confirmation. This approach is unusual as confirmation is generally required in assessment of disability in MS trials. Accordingly, a sensitivity analysis excluding the Reference ID: 4076435 Division Director Review Page 19 of 32 imputed data (21 events), consistent with the usual approach for a disability progression endpoint, was performed and failed to achieve a statistically significant treatment effect for CDP of either duration (p=0.1477 for 12 weeks and p=0.1884 for 24 weeks). Other sensitivity analyses of the primary endpoint are presented on pages 38 and 39 of Dr. Yan’s review and are largely consistent with the primary analysis. The concern regarding the imputation approach for the primary endpoint is that confirmed disability serves as a proxy for durably persistent disability and is intended to eliminate the contribution of fluctuations in disability to the disability outcome. Although the imputation approach was pre-specified, it was unusual, and, though a simple elimination of the imputed data weakened the result significantly, the trial itself provides a means to estimate the number of patients with imputed disability who would actually have gone on to have confirmation at week 12. We asked Dr. Yan to perform an additional sensitivity analysis based on this estimate. As her review addendum describes, about 23% of patients who had an initial onset of disability did not have it confirmed at 12 weeks. Based on this figure, 5 patients of the 21 who had imputed data could be expected to have an onset that is not confirmed, i.e., to not have an event, while 16 would have had an event. Dr. Yan conducted an analysis that selected 5 of the 21 patients randomly to be unconfirmed, with the remaining 16 contributing confirmed data to the primary analysis. This analysis was repeated 500 times, each with 5 randomly chosen patients to be assigned as unconfirmed. This table from Dr. Yan’s supplementary review describes the findings from this exercise.

-Dr. Yan describes the results of her sensitivity analyses of the T25FW on pages 45 and 46 of her review, and while only the sponsor’s analysis was significant (p=0.0404), she notes that the results of the sensitivity analyses appeared consistent regardless of which was used with marginally insignificant findings (p-values of 0.05 and 0.08).

-Dr. Yan notes that subgroup analyses by demographic and baseline characteristics were relatively consistent with the primary findings, with the exception of a lack of treatment effect seen in women on the primary outcome (12-week CDP of 35.5% in placebo and 36% in OCR), which represented about half of the enrolled population.

-Overall, the review team endorses somewhat differing opinions. Dr. Yan concludes that a statistically significant effect was shown on disability, both for the primary endpoint and for the analysis of the timed 25-foot walk, a related major secondary endpoint, and that OCR appears to delay disability progression in PMS patients. She notes that the evidence of effectiveness is weak, citing the loss of significance without imputation of disability events. I note that Dr. Yan came to this conclusion prior to the conduct of the additional sensitivity analysis described above that was informed by the actual pattern of confirmation seen in the study itself, and that maintained significance. I have discussed the result of this additional analysis with Dr. Yan and she agrees that her concerns about the loss of significance without imputation have been mitigated by the additional analysis and that the findings of the PPMS study support approval. Dr. Rodichok concludes that the PPMS study is an adequate and well-controlled study that provides evidence that OCR has a beneficial effect on disability, but, for reasons similar to those of Dr. Yan, feels the evidence is weakened by a lack of statistical persuasiveness. He also expresses concerns about the modest size of treatment effect and about the ability of the RMS studies to support the PPMS study, based on a lack of similarity in patient characteristics and disability findings in the two populations. Notwithstanding these concerns, he recommends approval for this population, in light of the unmet medical need for PPMS and acceptable safety profile of OCR. Dr. Marler does not recommend approval for the PPMS population. He cites several major concerns. First, he shares the concern of Dr. Yan and Dr. Rodichok regarding the statistical persuasiveness of the study, noting the issues with imputation and the loss of overall significance without imputation. As with Dr. Yan, Dr. Marler came to this conclusion prior to the conduct of the additional sensitivity analysis described above that was informed by the Reference ID: 4076435 Division Director Review Page 22 of 32 actual pattern of confirmation seen in the study itself, and that maintained significance. Dr. Marler also expresses concern about the lack of apparent effect on disability seen in the subgroup of women enrolled in the PPMS study, particularly in light of the signal for breast cancer. He does not comment on the notable effect in women (and men, for that matter) on relapses and MRI markers of disease activity in the PPMS population, limiting his assertion of an absence of effect in women to the primary outcome. Dr. Marler is concerned that the rate of events in the two arms of the PPMS study does not appear to differ over the majority of the study, with most of the effect being apparent soon after treatment. He notes that adherence to the protocol was not ideal, with deviations from instructions concerning the need to record baseline scores before randomization. He expresses concern about missing data, an unfortunately common issue. For these reasons, he finds the PPMS study not well-controlled and not persuasive. Like Dr. Rodichok, Dr. Marler also expresses concern about the ability of the RMS studies to support the PPMS study, based on a lack of similarity in patient characteristics and disability findings in the two populations, as well as the inability of other drugs that have succeeded in RMS to show an effect in PPMS. I agree with Dr. Yan and Dr. Rodichok that the results of the PPMS study support approval. I do not agree with Dr. Marler that the PPMS study does not contribute to substantial evidence of effectiveness. I do not agree with Dr. Rodichok or Dr. Marler that the PPMS study results must be viewed in isolation from the RMS results. I describe my reasoning below.

-As noted, a single dose regimen was evaluated. After an initial dose of two 300 mg infusions given 14 days apart, subsequent doses were single 600 mg infusions every 6 months. The effect on annualized relapse rate in both studies was highly significant with a reduction of 46- 47% against Rebif, a drug with an established effect on annualized relapse rate. The effect on accumulation of sustained disability, measured by comparing confirmed disability progression endpoints, was also highly significant in both studies, despite an expected need to assess disability by pooling data from both studies. This pooled analysis was the major secondary endpoint and was highly significant, with an absolute reduction of about 5% compared to Rebif, a drug with an established effect on disability. The effects on relapse and disability were supported by consistent effects on various secondary, subgroup, and sensitivity analyses. The members of the review team all agree that the RMS studies provide substantial evidence of effectiveness for the treatment of RMS. The review team is in partial agreement (as noted, Dr. Marler dissents) that the applicant has provided substantial evidence of effectiveness for the use of OCR for the treatment of patients with primary progressive multiple sclerosis. This conclusion is primarily supported by evidence from a single study in PPMS (Study WA25046) that evaluated the use of a single dosing regimen of OCR, with additional support from results of the RMS studies described above. This PPMS study evaluated a primary outcome of time to confirmed disability progression, comparing OCR to placebo. Reference ID: 4076435 Division Director Review Page 27 of 32 Again, a single dose regimen was evaluated, though it differed slightly from the RMS studies in that all doses in the PPMS study were given as two 300 mg infusions given 14 days apart every 6 months. The effect on confirmed disability progression was significant (p=0.03) with a reduction of 24% compared to placebo. Important secondary outcomes of disability progression sustained for 24 weeks, T25FW, and MRI T2 lesion volume were all significant. Despite concerns regarding an unusual imputation of confirmed disability progression in the absence of an actual measurement (i.e., patients that had an initial event of disability progression but left the study before progression could be confirmed at a second visit 12 weeks later were imputed as confirmed disability progression endpoints), a sensitivity analysis performed by Dr. Yan based on assignment of the imputed endpoints to an event status (i.e., contributing to the count of confirmed disability progression or being censored at the time of withdrawal) based on the actual proportion of confirmed disability progression events in patients that had an initial event of disability progression observed in the study was supportive of primary outcome. Also, a reduction in the occurrence of relapse favoring OCR was seen in the PPMS study. The members of the review team are not unanimous with regard to the evidence that the PPMS study provides, as I noted above. Dr. Yan and Dr. Rodichok support approval for PPMS, while Dr. Marler argues against it. Dr. Marler expresses concern not only about the strength of the PPMS study, but he also doubts the ability of the RMS studies (which showed an effect on disability progression in RMS) to support the PPMS study, leading him to conclude that the PPMS study must be considered on its own. Dr. Rodichok shares concerns about the about the ability of the RMS studies to support the PPMS study, but recommends approval based on the results of the PPMS study and the unmet medical need in this area. Whether the RMS studies may serve to support the PPMS study deserves some comment in light of the extensive assertions of Dr. Marler and Dr. Rodichok that they cannot.