Multiple Sclerosis Research Repository

Dear FDA:

Per FDA Guidance, “Breakthrough Therapy Designation qualifying criteria” is as follows: “A drug that is intended to treat a serious condition and that preliminary clinical evidence indicates may demonstrate substantial improvement over available therapies on a clinically significant end point or end points.”  The features of “Breakthrough Therapy Designation” are more than those Fast Track Designation, Accelerated Approval Pathway, or Priority-Review Designation.  Thus, this Breakthrough Therapy Designation is the most desired and advantageous by and to the pharmaceutical company applicants when they submit NDAs.  

Ocrelizumab/Ocrevus received this Breakthrough Therapy Designation, and I am requesting an explanation as to on what grounds, please, because the FDA approval documentation for ocrelizumab do not support that ocrelizumab met the qualifying criteria for Breakthrough Therapy Designation: “For relapsing MS, the unmet need is a drug or drug combination that prevents long-term disability better than available treatments and does so with fewer adverse effects.  Ocrelizumab does not meet an unmet need for relapsing forms of MS because there are so many other FDA-approve drugs that meet the same need.  None of the approved drugs for relapsing MS prevents the occurrence of relapses or stops progression of disability.  For PPMS, the unmet need is a drug that slows progression of disability (CDER, Application Number: 761053Orig1s000, Medical Review(s), Cross Discipline Team Leader Review, Benefit-Risk Assessment, pages 5-6).  

Based on the above-cited information from the FDA’s ocrelizumab Medical Review, one can see how ocrelizumab would POSSIBLY have qualified for Fast-Track Designation, under the following criteria: “A drug that is intended to treat a serious condition and for which nonclinical or clinical data demonstrate the potential to address an unmet medical need.”  I say “POSSIBLY” here because the language says “nonclinical or clinical data demonstrate the potential to address an unmet medical need”: it is highly debatable as to whether the clinical data from WA250046 “demonstrate the potential to address an unmet medical need.” 

Why was ocrelizumab not given Fast-Track Designation, then, and was instead given Breakthrough-Therapy Designation?  Under what criteria did ocrelizumab meet the criteria for Breakthrough-Therapy Designation?  

Also, when it was known that the data for the PPMS ocrelizumab trial (WA25046) had numerous issues that caused the FDA to note in the Medical Review that the trial was not adequate and well controlled; that the results were not persuasive; that there were numerous methodological and bias issues in this trial; etc, why did the FDA not rescind the Breakthrough-Therapy Designation?  

I look forward to your thorough, comprehensive and satisfactory answers to these questions.

-From: “Center for Drug Evaluation and Research, Application Number: 761053Orig1s000, Medical Review(s)” (Ocrevus/ocrelizumab)

Instances where this document says the PPMS trial WAS “adequate and well-controlled” and WAS NOT “adequate and well-controlled” (contradictory!!!)

-From: “Center for Drug Evaluation and Research, Application Number: 761053Orig1s000, Medical Review(s)” (Ocrevus/ocrelizumab)

1. “Trial WA25046 is not well-controlled…” (Cross Discipline Team Leader Review, Benefit-Risk Analysis, p 4)

2. “Dr. Rodichok agrees that it (PPMS trial WA25046) is adequate and well-controlled” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, 44)

3. “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, 45)

4. “-The trial is adequate and well-controlled” (Cross Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy, 54)

5. Primary progressive MS: A single adequate and well-controlled trial…” (Clinical Review, Benefit-RIsk Summary and Assessment, 18)

6. “In a single adequate and well controlled trial [WA25046]…” (Clinical Review, Benefit-RIsk Summary and Assessment, 22)

1. “…in an adequate and well controlled trial [WA25046]…” ((Clinical Review, Benefit-RIsk Summary and Assessment, 22)

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)

From: “Table 126: Reviewer table: Proportion of patients with CDP12 or CDPW12 by subgroup, WA25046 [PPMS trial [ORATORIO]], ITT [intention to treat]” (From: Center for Drug Evaluation and Research, Application Number: 761053Orig1s000: Medical Review(s))

1. Subgroup: Female; Treatment Effect 0.6%
2. Subgroup: Male; Treatment Effect: 5.9%
3. Subgroup: age 45 or less; Treatment Effect: 5.1%
4. Subgroup: older than 45; Treatment Effect: 1.4%
5. Subgroup: less than 75kg; Treatment Effect: 2.7%
6. Subgroup: 75kg or greater; Treatment Effect: 3.9%
7. Subgroup: 2 years or less time since diagnosis: Treatment Effect: 7.2%
8. Subgroup: 2 to 5 years since diagnosis: Treatment Effect: -1.2%
9. Subgroup: 5 to 10 years since diagnosis: Treatment effect: 0%
10. Subgroup: more than 10 years since diagnosis: 0.4%
11. Subgroup: less than or equal to 3 years since onset of MS symptoms; Treatment Effect: 4.7%
12. Subgroup: 3 to 5 years since onset of MS symptoms: Treatment Effect: 0.2%
13. Subgroup: 5 to 10 years since onset of MS symptoms; Treatment Effect: 1.6%
14. Subgroup: greater than 10 years since onset of MS symptoms; Treatment effect: 0%
15. Subgroup: 0 baseline T1 Gd enhanced lesions; treatment effect: 4.3%
16. Subgroup: 1 baseline T1 Gd enhanced lesions; treatment effect: -1.4%
17. Subgroup: 2 baseline T1 Gd enhanced lesions; treatment effect: 2%
18. Subgroup: 3 baseline T1 Gd enhanced lesions; treatment effect: 1.4%
19. Subgroup: 4 or more baseline T1 Gd enhanced lesions; treatment effect: 0.2%
20. Subgroup: baseline EDSS under 4; treatment effect: 3.1%
21. Subgroup: baseline EDSS 4 or above; treatment effect: 3.5%
22. Subgroup: baseline EDSS less than or equal to 5; treatment effect: 4.5%
23. Subgroup: baseline EDSS above 5; treatment effect: 2%
24. Subgroup: relapse free, yes; treatment effect: 2%
25. Subgroup: relapse free, no; treatment effect: 4.5%
26. Subgroup: previous MS treatment, yes; treatment effect: 2.5%
27. Subgroup: previous MS treatment, no; treatment effect: 4.1%
28. Subgroup: outside of the USA; treatment effect: 4.7%
29. Subgroup: USA; treatment effect: 1.8%

https://pmc.ncbi.nlm.nih.gov/articles/PMC8917050

1. “Salaries, payroll taxes, and benefits” more than doubled from 2016 to 2017 ($35,773,829 and $83,608,658 respectively).  However, from 2016 to 2017, “awards, grants, and prizes” including research grants and fellowships only increased by $5,988,539. 

2. This information indicates that the amount of money the NMSS has spent on “salaries, payroll taxes, and benefits” has generally increased, while “awards, grants and prizes” amount has generally decreased.  This is concerning.  

3. Per the 2023 financial information, the amount spent on “salaries, payroll taxes, and benefits” was more than double that spent on “awards, grants, and prizes”

4. In 2015 and 2016, the amount spent on “awards, grants and prizes” was more than the amount spent on “salaries, payroll taxes, and benefits”; however, as of 2017, the opposite has been true
5. It is concerning that the “travel, conferences, and meetings” expenses approximately quadrupled from 2016 to 2017 ($3,265,938 and $13,661,776, respectively)
6. *Disclaimer: apologies if any of my numbers are wrong; I did double-check them*

From “EAE is not a useful model for demyelinating disease” by Peter O Behan and Abhijit Chaudhuri (2014):

-“Immunosuppression clearly works in EAE but its transposition to humans, which has a theoretical appeal, has not been proven to be efficacious in MS. The claims that it may work in MS have been tested, and none as well as by the Myloral trial”

-“Immunosuppression in MS carries another heavy burden, namely the development of PML and other serious side effects. If little is known about cause, then it is troubling that a drug therapy can be suggested at all. Why should patients mildly affected with MS, which is the majority, take such potentially dangerous drug cocktails? In our opinion there is no treatment for MS, although a temporary benefit may occur with steroids due predominantly to its effect on oedema”

-“There is no specific and confirmed evidence that shows that EAE bears any relationship to MS”

-“…the evidence in RMS drug labels for a reduction in disability progression shows smaller effect sizes and lacks confirmation in a second trial for some drugs” (Cross Discipline Team Leader Review, Product Quality, page 4)

-Rebif showed a reduction in patients with disability progression sustained for 3 months in 8 to 11 percent of patients (page 4)

-Review the images of this table and notice that under the “Efficacy Information” column only 2 DMTs have efficacy information about reduction in disability (Mitoxantrone and Ocrelizumab for PPMS) (*The claim here of Ocrevus showing a “24% reduction in disability progression (primary progressive MS)” is not accurate and has been discussed in previous posts*)

FDA Approval Package for Copaxone (NDA 20-622/S-015) (Approval Date: 7-2-2001)

1. From FDA Copaxone Label 020622s057lbl.pdf: “Table 4: Study 4 MRI Results: Medians of the Cumulative Number of T1 Gd-Enhancing Lesions: Copaxone (N=119): 11; Placebo (N=120): 17; P-Value: 0.0030
2. *What study is Study 3 in this label? -appears to have been the PRECISE trial
3. It is unsettling and disturbing that the FDA approved the labeling changes to Copaxone:
   1. “The objective raises the concern that human subjects were asked to participate in a medical experiment that was not necessary” (p 31/68)
   2. “Protocol 9003 was not based on a genuine uncertainty that the placebo group would have fewer MRI lesions than the Copaxone-treated group; it was already known that Copaxone reduced relapses, and that relapses are associated with T1 Gd-enhancing lesions” (p 31/68)
   3. “Unfortunately, the protocol shows that there was never any intention to attempt definitive answers to clinical questions, particularly the correlation between MRI and clinical parameters” (p 32/68)
   4. “Even if sponsor can overcome ethical concerns regarding the necessity of Protocol 9003, sponsor next stumbles on the problem of informed consent” (p 32/68)
   5. “A careful reading of some of the informed consent documents (they vary in significant ways among the 29 participating centers)…” (p 32/68)
   6. “But many forms eliminated all reference to the most significant Copaxone trial (9001).  In plain language, the purpose of 9003 was to determine the effect of Copaxone on the MRI; the clinical effect was already proven.  Prospective participants should have been told this.  Because they were not, the required element of informed consent, a statement of purpose,was absent” (p 32/68).  
   7. “The FDA must refuse to grant an NDA application if the applicant has not complied with its regulations concerning informed consent.  No informed consent form used in this study gave a clear explanation of the study’s true purpose…Most were inadequate in describing alternatives…This would have been especially valuable information to Canadian patients…” (p 33/68)
   8. “…I believe the necessity was marginal at best, and sponsor failed to counterbalance this weak necessity by making sure the investigators gave completed and accurate informed consents” (p 33/68)
   9. “In summary, the objective of 9003 was ethically flawed in that it recruited patients to participate in a study that was not necessary.  From a regulatory standpoint, the protocol violated the requirements of informed consent that are required for NDA approval, and must be refused pursuant to 21 CFS Statute 314.125(16), Statute 50.20, Statute 50.25, and Statute 50.27 if conducted under an IND…” (p 34/68)
   10. “Initially patients who had previously participated in an Oral Myelin Trial were excluded from the 9003, but the exclusion was later amended.  The amendment states that the reason for letting patients who participated in the Oral Myelin Trial participate in 9003 is because it ‘showed no clinical efficacy.’  This is a design flaw, in that the possibility of a synergistic effect between oral myelin and Copaxone cannot be excluded.  If any patients were admitted to 9003 who had received oral myelin, the possibility of a confounding variable was introduced.  Data was to which patients, if any, received oral myelin, was not provided in this submission” (p 34/68)
   11. Twenty-seven patients received steroids in violation of the protocol during the study…Other violations included using doses in excess of 1000 mg methyprednisoone IV for 3 days, unusual routes of administration (IM, intrathecal), for indications other than documented acute MS exacerbations” (p 35/68)
   12. “Another important protocol violation involved missed MRI scans” (p 35/68)
   13. “Because the data were not normally distributed, a parametric method such as was used here, was inappropriate…the highly skewed data” (p 36/68)
   14. “Biostatistics also finds that the use of adjusted means, which was done with every endpoint, was also inappropriate…The adjusted means in the proposed labeling were from invalid models and are therefore, not appropriate and misleading…the normal assumption was severely violated…In addition to the violation of the normal assumption, covariates other than those specified in the protocol were added to the model.  Therefore, in this reviewer’s opinion, all adjusted means should be removed from the labeling” (p 36/68)
   15. “There was no significant difference between the drug and placebo groups on this MRI endpoint” (the endpoint was: “proportion of T1 Gd-enhancing lesion-free patients, which was not an endpoint in the original protocol, but sponsor states it is the complementary value of the proportion of patients with Gd-enhancing lesions” (p 37/68)
   16. “…sponsor…used a parametric method inappropriate to the highly skewed data” (p 37/68)
   17. “The total number of new Gd-enhanced lesions in T1-weighted images was not normally distributed and therefore the parametric method used by sponsor was ot appropriate” (p 37/68)
   18. “…the latter approach is unsuited to these data, which are highly skewed” (p. 37/68)
   19. “If one uses the rank-transformed data, however, none of the secondary endpoints are significant” (p 38/68)
   20. “The results of 9003 are fruits of a study tainted by patient consent that was ot properly informed” (p 39/68)
   21. “…this reviewer recommends the sponsor be strongly reminded of the legal requirements for informed consent.  Whether the more drastic action of excluding some patients’ data (e.g., the Canadians’) from the analysis, or even barring any reference to the MRI Protocol 9003 in the labeling has been discussed internally in the Division.  The consensus is that the behavior was not egregious, pervasive, or reckless enough to warrant the more drastic remedies” (p 39/68)
   22. “In any discussion about preventing a sponsor from harvesting the fruits of an ethically-tainted protocol, one needs to keep in mind the potential that the Agency’s action may have unwanted effects on the public.  However, the medical community relies more on medical literature than on labeling as a source of new medical knowledge; labeling issues matter to a sponsor in large part because they form the basis for promotional claims.  Therefore, depriving a sponsor of the fruits of an ethically-flawed study harms the sponsor economically; the medical literature and its readers are unlikely to be harmed” (P 39/68)