Multiple Sclerosis Research Repository

FDA Ocrevus Approval: RRMS (Center for Drug Evaluation and Research, Application Number: 761053Orig1s000, Medical Review(s))

1. “RMS: the benefit of treatment with OCR 600 on relapses and short term disability is persuasive and justifies the modest and manageable risk…” (Clinical Review, 21-22)
2. “There are no data to support that treatment with OCR has a clinically meaningful effect on long term irreversible disability” (Clinical Review, 22) 
3. “The two pivotal trials [for RRMS] also demonstrate a statistically significant reduction in the relatively small proportion (~10%) of patients with RM who experience periods of short term disability (Clinical Review, 19) 
4. “Treatment with OCR 600 results in a statistically significant and clinically meaningful reduction in relapses and in the occurrence of short term periods of disability largely unrelated to relapses” (Clinical review, 19)
5. “The benefit of currently approved therapies [for RRMS] on short term disability has been inconsistent.  There is a need for a therapy with robust evidence of a reduction in these measures of disability (Clinical Review, 21)
6. “Protocol Violations/Deviations [in RRMS trial WA21092]: 41 subjects did not meet all eligibility criteria…”
7.  “EDSS Cleaning Process (SAP version 4 Section 3.3)  Review Comment: In describing the EDSS ‘cleaning’ process in Appendix 1 of the SAP it is stated that ‘Between Jan 1, 2011 and Jan 31, 2012…Experts reviewed 1082 EDSS assessments rated by 267 examining investigators at 160 study sites participating in the Roche trials WA25046, WA21092 and WA21093.  They found in 23% of the cases inconsistencies in the last step of the assessment, namely the combination of the Functional Systems and the ambulation scores to the final EDSS step.’  This new process was applied to all previous and following EDSS scores.  The sponsor subsequently proposed the ‘cleaning’ process in an amendment dated February 25, 2013.  DNP provided written comments to the proposed procedure and essentially agreed that the process was acceptable (see letter to sponsor dated 3/21/13)” (Clinical Review, 136)
8. “Reviewer Comment [WA21092]: The time interval from the onset of the relapse to the clinical assessment is not ideal…It is unclear however what effect, if any, the delay in assessment of relapses may have had on the overall results of the trial” (Clinical Review, 65)
9. “[WA21092]  The difference in proportions with a CDP24 event shows a reduction with OCR 600 treatment that is not quite statistically significant.  The relative reduction is 40% without or with imputation of the CDPW24 events” (Clinical Review, 71)
10. “[WA21092]  The duration of any given progression meeting the criteria for an IDP is shown in Table 34.  There is no difference between the treatment groups for this measure of periods of disability although there are more such periods in the Rebif group compared to the group treated with OCR 600” (Clinical Review, 73)
11. “[WA21092]  Reviewer Comment: In these exploratory analyses it appears that treatment with OCR 600 may not affect the duration of a period of disability.  Rather, treatment with OCR 600 reduces the number of such episodes” (Clinical Review, 74)
12. “[WA21093]  Protocol Violations/Deviations: 35 subjects did not meet all eligibility criteria…There were 11 and 12 protocol violations in the OCR 600 and Rebif groups respectively, all related to administration of study drug” (Clinical Review, 84)
13. “[WA21093]  Reviewer Comment: A prolonged screening period is not ideal…One concern is that the level of disability may have changed since enrollment” (Clinical Review, 85)
14. “[WA21093]  Reviewer Comment: The time interval from the onset of the relapse to the clinical assessment is not ideal…The intervals are about 2 days later than those in WA21092.  The confirmation rates are lower compared to those in WA21092…It is unclear however what effect, if any, the delay in assessment of many relapses may have had on the overall results of the trial” (Clinical Review, 94)
15. “[WA21093]  The difference in proportions shows a reduction with OCR 600 treatment that is not quite statistically significant [re: the simple proportion of patients in the ITT with a 12 week confirmed progression of disability] [p-values: 0.0620 and 0.0624]”
16. “[WA21093]  The difference in proportions show a reduction with OCR 600 treatment that is not quite statistically significant [the simple proportion of patients in the ITT with a 24 week confirmed progression of disability]” (Clinical Review, 100)
17. “Efficacy Conclusions for the RMS indication:…this review concludes that, despite concerns about dropout and bias due to treatment-disclosing side effects…” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, 26)
18. “3.  Product Quality…The team has identified serious concerns with drug product stability and potency at the time of the filing meeting….They have found no satisfactory resolution to the drug substance manufacturing and potency issues.  One of the issues is degradation of one of the drug product excipients (polysorbate 20) and drug product stability.  At the 18 month time point, all three batches contain visible particles, which Genentech indicates are composed of free fatty acid (a polysorbate breakdown product).  The other issue is variable potency among different drug lots” (Cross Discipline Team Leader Review, Clinical Pharmacology, 13)