Multiple Sclerosis Research Repository

FDA Bad Ad Complaint about Ocrevus for PPMS

-Date: 2-24-2025

1. From Ocrevus for HCP website:
   1. Doesn’t list pancreatitis and depression and suicide under “Warnings and Precautions,” despite the FDA approval documentation for Ocrevus showing that these occurred in those treated with Ocrevus

-Commentary: 

1. “6.  Pancreatitis.  Drs. Boehm and Yasuda consider it significant the pancreatitis occurred in 5 ocrelizumab treated patients and none in the comparator subjects in controlled trials…” (Cross Discipline Team Leader Review, Safety, 63)
2. “4. Depression and Suicide.  Dr. Boehm states that serious depression and suicide attempts occurred only in ocrelizumab patients and not in comparator patients in the MS controlled trials…Therefore, because Rebif labeling has a warning about depression and suicide, Drs. Boehm and Yasuda agree that there should be a similar warning for ocrelizumab” (Cross Discipline Team Leader Review, Safety, 63)
4. From Ocrevus for Patients website: Under “What are the possible side effects of Ocrevus and Ocrevus Zunovo?”: It doesn’t list: pancreatitis and depression and suicide

-Commentary:

1. “6.  Pancreatitis.  Drs. Boehm and Yasuda consider it significant the 

pancreatitis occurred in 5 ocrelizumab treated patients and none in the 

comparator subjects in controlled trials…” (Cross Discipline Team Leader 

Review, Safety, 63)

2. “4. Depression and Suicide.  Dr. Boehm states that serious depression and suicide attempts occurred only in ocrelizumab patients and not in comparator patients in the MS controlled trials…Therefore, because Rebif labeling has a warning about depression and suicide, Drs. Boehm and Yasuda agree that there should be a similar warning for ocrelizumab” (Cross Discipline Team Leader Review, Safety, 63)

3. From Ocrevus for Patients website:
4. “Ocrevus was proven to delay disability progression of PPMS.  People taking Ocrevus were 24% less likely to have disability progression than those taking placebo*!  32.9% of people taking Ocrevus had disability progression compared with 39.3% of those taking placebo.*”

-Commentary: The information from the 1 clinical trial (WA25046/”ORATORIO”) contained in the FDA approval documents states that the above-cited information is extremely questionable, as it was not the result of an: “adequate and well-controlled trial”; that the results were not “persuasive”; that there numerous bias and methodological issues in this trial; and many other concerning aspects that make the results cited above extremely suspect and highly unlikely 

-Some examples:

i) “Conclusion: the PPMS trial is not well-controlled” (Cross Discipline 

Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 44)

ii)  “This review concludes that would be reasonable to decide that the 

WA25046 trial [ORATORIO] is not adequate or well-controlled” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 44)

iii) “The conclusion of this review is that the PPMS Trial WA25046 does not provide persuasive evidence of effectiveness” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 44)

i) “The conclusion of this review is that the PPMS Trial WA25046 does not 

provide persuasive evidence of effectiveness” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 46)

ii) “In the trial, there is no benefit of treatment with ocrelizumab in women, 

numerically or statistically” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 39)

i) “The conclusion of this review is that the PPMS trial is not a single multicenter study of excellent design that provides highly reliable and statistically strong evidence of an important clinical benefit as described in the Guidance on Clinical Evidence quoted above” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 46)

iv) “”Given the weakness of the evidence from the PPMS trial to support 

the effectiveness of ocrelizumab…” (Cross Discipline Team Leader 

Review, Clinical and Statistical Reviews of Efficacy, p. 46)

ii) “The conclusion of this review is that the PPMS trial WA25046 does not provide persuasive evidence of effectiveness” ( “The conclusion of this review is that the PPMS trial is not a single multicenter study of excellent design that provides highly reliable and statistically strong evidence of an important clinical benefit as described in the Guidance on Clinical Evidence quoted above” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 45)

i) “This review concludes that it would be reasonable to decide that the WA25046 trial is not adequate or well-controlled” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 45)

i) The ORATORIO study was found not to adequately control bias (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 44)

ii) “…the results of the trial…are not statistically significant without imputation of primary outcome events.  Also, the absolute reduction in the proportion of patients who experience these events is less than 5%, and because over 30% of patients experience progression events after two years of treatment with ocrelizumab” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 45)

iii) “Dr. Yan notes that the use of imputation weakens the evidence of 

reduction in disability progression in the PPMS trial.  The two RMS trials 

did not use imputation, which is the usual method in MS trials” (Cross 

Discipline Team Leader Review, Clinical and Statistical Reviews of 

Efficacy, p. 45)

i) “Table 14: Concerns with Design, Conduct, and Data Quality for the PPMS 

Trial” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 39)” noted 5 significant concerns: Imputation of primary outcome events; No treatment benefit for female patients; Lack of treatment effect after 18 weeks as seen in Kaplan-Meier curve of primary outcome; High rate of dropout and missing outcomes; and Determination of Baseline Primary Outcome Measure of Baseline after Recorded TIme of Randomization and Infusion

ii) “The ____ (greyed out) identified 18 problems; 6 major, and one critical (the over-enrollment mentioned above).  Other problems included the quality system, conduct and management (over-enrollment, vendor management, primary endpoint), data management (design and requirements of electronic data capture), and monitoring and auditing.  The inspection team concludes that the PPMS trial ‘was not conducted fully in line with the requirements of the applicable European directives, guidelines, and national legislation’” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 39)

iii) “In 29% of patients, investigators reported the baseline EDSS after infusion of the study drug and in 67% after randomization.  THis represents an unusually extensive failure of investigators to follow fundamental principles of clinical research…” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, p. 39)

iv) “…the evaluation of the MRI end points, SF-36, and T25FW were conducted with a subset of randomized patients.  The rationale for reporting that these analyses were conducted in the ITT population is unclear.  There was a considerable amount of missing data for these outcome measures (e.g., data for change in brain volume were missing for approximately 35% of randomized patients by week 120), and the impact of this missing data is uncertain.” (CADTH, Clinical Review Report, May 2018)

v) “…the limitations of the subgroup analyses in the ORATORIO trial (e.g., non-powered analyses excluded from the statistical analysis hierarchy)…” (CADTH, Clinical Review Report, May 2018)

vi) “Similar to the results for disability progression, the results for the T25FW test were sensitive to the method of imputation that was used to handle missing values.  Sensitivity analyses conducted by the FDA demonstrated that changes in the imputation method resulted in the results being non-significant.” (CADTH, Clinical Review Report, May 2018)

vii) “There was a considerable amount of missing data for these outcome measures (volume of T2 lesions, new and enlarging T2 hyperintense lesion count, Gd-enhancing lesion count, and brain volume).  For example, data for change in brain volume were missing for approximately 35% of randomized patients (i.e., the ITT population) by week 120” (CADTH, Clinical Review Report, May 2018)

viii) “Key limitations with the ORATORIO trial included the following: sensitivity of the results for 12-week CDP (primary end point), 24-week CDP (secondary end point, and T25FW to different methods and assumptions regarding the imputation of missing data; the unplanned increase in sample size (i.e., from 630 to 732); the large and disproportionate rate of withdrawal across the study (i.e., 33.6% and 20.7% in the placebo and ocrelizumab groups, respectively); the potential for unblinding due to the AE profile of ocrelizumab (particularly events related to the administration of the study drug); and the need to impute a large amount of the data for some end points (e.g., SF-36 and changes in lesions)” (CADTH, Clinical Review Report, May 2018)