Multiple Sclerosis Research Repository

April 4, 2025

Via Email: guidelines@aan.com and rae-gra@ccf.org

In Re: “Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology”

Dear AAN Guidelines and Dr. Rae-Grant:

I am writing this letter to express my feedback and concern about the following document: “Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis” published by AAN in 2018 and authored by Dr. Rae-Grant et al.

For the purposes of this letter, I will be addressing “Starting: Recommendation 17,” which states in part: “ Rationale[:] Ocrelizumab is the only DMT shown to alter disease progression in individuals with primary progressive MS (PPMS) who are ambulatory.” and “Statement 17,” which states: “Clinicians should offer ocrelizumab to people with PPMS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits (Level B)” (p. 781).

First, I will offer my response to this document’s claim that “Ocrelizumab is the only DMT shown to alter disease progression in individuals with primary progressive MS (PPMS) who are ambulatory”:

Per the ORATORIO clinical trial (the sole clinical trial that formed the basis for the FDA’s very questionable and apparently non-compliant with statutory regulations and their own internal agency Guidance documents; referred to as WA25046 in the FDA Ocrevus approval documentation):

 From “Cross-Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy (Reference ID: 4019179”) (source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761053orig1s000medr.pdf):

1. “Credibility of a trial’s results can be lost in small increments…the review team became aware of problems with the results, the trial conduct, and the protocol that significantly diminished the review team’s confidence in the results of the trial.  Table 14, below, enumerates the more significant of these weaknesses” (p 38)

2. These “more significant of these weaknesses” were:
   1. Imputation of primary outcome events
   2. No treatment benefit for female patients
   3. Lack of treatment effect after 18 weeks as seen in Kaplan-Meier curve of primary outcome
   4. High rate of dropout and missing outcomes
   5. Determination of Baseline Primary Outcome Measure of Baseline after Recorded Time of Randomization and Infusion (p 39)

3. “Without changing the protocol, the applicant increased the sample size in the PPMS trial by 102 patients from 630 to 732.  The trial results would be negative if the analysis uses the first 630 patients (p=0.0087)” (p 39)

4. “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” (p 40). 

5. “The trial protocol did not adequately control bias” (p 44)

6. “Some unusual features of the trial results may be due, in part, to a small treatment effect and a high and unbalanced loss of primary outcome data” (p 44) 

7. “The number of patients with missing possible outcomes exceeded the absolute difference observed in the trial (maximum of 7.1% absolute difference in Kaplan-Meier estimate and minimum dropout rate of 20%).  For these reasons, the trial does not contain a sufficient quantum of evidence to have confidence that the results are accurate.  One could possibly explain these unusual results by simple chance, but that same argument would apply to the primary outcome as well.  An adequate trial would not be likely to have these uncertainties.” (p 44)

8. “This review concludes that it would be reasonable to decide that the WA25046 trial is not adequate or well-controlled” (p 45)

9. “The conclusion of this review is that the PPMS Trial WA25046 does not provide persuasive evidence of effectiveness” (p 45)

10. “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” (p 46)

11. “Dr. Rodichok and Dr. Yan agree that the evidence to support an effect on disability progression in PPMS from trial WA25046 is weak” (p 54)

12. “For PPMS, this review agrees with Dr. Rodichok that the evidence is not convincing that ocrelizumab is effective and with Dr. Yan that the evidence of effectiveness is weak, particularly in women” (p 55)

Please also refer to my recently-submitted FDA Citizen Petition which requests that the FDA rescind their approval of Ocrevus for PPMS due to the fact that it appears the FDA violated the statutory regulation standard of “substantial evidence of effectiveness” when the agency approved Ocrevus for PPMS: https://www.regulations.gov/document/FDA-2025-P-0547-0001.

Even if the outcome of this trial were valid (we would accept the data reported in the ORATORIO trial, even though the FDA found it to be invalid), Ocrevus for PPMS showed a very small absolute risk reduction of 6.4% for 12-week CDP, which results in a Number Needed to Treat (NNT) of 16, which is not meaningful or significant at all.  Also, it is not valid to say that the results of this trial (which were again flawed and invalid) evidence that “Ocrelizumab is the only DMT shown to alter disease progression in individuals with…(PPMS)” because MS is a lifelong progressive, neurodegenerative disease; evidence that Ocrevus affected 12-week CDP (which was again invalid) does not mean that it will affect disease progression over the course of this lifelong illness.  

Second, I will offer my response to this document’s claim that “Clinicians should offer ocrelizumab to people with PPMS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits (Level B)”

In regards to the “Level B” classification that is given to the above claim, “Level B corresponds to the helping verb should.  Such recommendations are more common, as the requirements are less stringent but still based on the evidence and benefit-risk profile” (p 778).

As evidenced by the information that I provided above regarding the lack of evidence of efficacy of Ocrevus for PPMS from the ORATORIO/WA25046 clinical trial, this claim (“Clinicians should offer ocrelizumab to people with PPMS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits”) most certainly does NOT meet the criteria of “…still based on the evidence and benefit-risk profile.”  It is clear that the benefits of Ocrevus for PPMS (especially for women, in whom no treatment benefit was found) do NOT outweigh the risks.  

I look forward to your response to my feedback and concerns expressed in this letter, and please await future correspondence regarding other concerning aspects of this “Practice guideline recommendations summary.”