The Medical Partnership 4 MS (mp4MS) is committed to advocating for multiple sclerosis (MS) patients in the United States by engaging the varied stakeholders. The mp4MS is composed of neurologists and allied health professionals dedicated to the treatment and management of patients with MS.

A lot of changes are happening in access to care in 2014 and beyond. The best way to protect the entire MS community is for us to work together. By sharing your access issues, we can help advocate for the entire MS community. Your name and other personal information will not be shared with anyone (unless YOU want it to be), but putting all the access stories together may be helpful in advocating for the entire MS community.


Below is a response from the Medical Partnership 4 MS to a draft document made for the Agency for Healthcare Research and Quality (AHRQ) that that may be used an excuse to take you off of your MS medications.
Draft AHRQ Guideline on Discontinuing MS medications

Medical Partnership 4 MS
6 Fairfield Blvd., Suite 11
Ponte Vedra, FL 32082

Nov. 4, 2014

Suchitra Iyer, Ph.D.
Task Order Officer
Center for Evidence and Practice Improvement
Agency for Healthcare Research and Quality
540 Gaither Road
Rockville, MD 20850

RE: Comments on Discontinuation of Disease-Modifying Treatments for Multiple Sclerosis

Dear Dr. Iyer:

Thank you for inviting public comment on the draft comparative effectiveness review on the subject of discontinuation of disease-modifying treatments for multiple sclerosis. The Medical Partnership 4 MS (MP4MS) is committed to advocating for multiple sclerosis (MS) patients throughout the United States by engaging the varied stakeholders. The MP4MS is composed of neurologists and allied health professionals dedicated to the treatment and management of patients with MS.

The Medical Partnership 4 MS has analyzed the draft EPC document on discontinuation of disease-modifying treatments for multiple sclerosis, and multiple errors and omissions have been found. In addition to a misrepresentation of the evidence (or lack thereof) surrounding non-patient-centered justifications for discontinuation of MS disease-modifying treatments, the Evidence-based Practice Center (EPC) did not adequately seek input from experts in the field prior to posing the Key Questions.

While it may or may not be the standard operating procedure of the AHRQ to not disclose the identities of the EPC and its Technical Expert Panel in a draft version of a proposed guideline, the statement on page ii that “[n]one of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report” is impossible to verify. A request for public comment should be akin to a scientific peer review in that the reviewers (members of the public) have a right to know who the authors are, their affiliations, their financial conflicts of interest, as well as their non-financial biases. A recent JAMA (Journal of the American Medical Association) article[i] highlights the need for authors to disclose more than merely their financial conflicts; the medical ethicist recommends that authors also disclose other relevant biases.  By removing the Acknowledgments, Key Informants and Technical Expert Panel from the draft document, the AHRQ is at risk for withholding vital and relevant information from the public,  which in turn places the AHRQ at risk for not meeting the stated congressional mandate of the AHRQ and its responsibilities to the U.S. citizenry. Furthermore, recent and historical examples of discredited scientific publications and “experts” have made it crucial for knowledgeable specialists to review the credentials and publication history of those involved in creating a draft document (intended to be used in guideline development) that will have a profound (and potentially devastating) effect on patients and their families.

We feel that the AHRQ does not fully grasp the dangers inherent in the statement on page ii that “[t]his report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies.” Specifically, using derivatives of a literature review has the potential to drastically change its intent and conclusions. Thus, if there is even one errant statement in such a document, then it may be inappropriately used to come to conflicting conclusions. This has the potential to harm the very people that AHRQ is supposed to be protecting, the American patients.

In the preface (page iii), there is a misrepresentation concerning the nature of evidence-based practice, since the draft document implies that systematic reviews are more central than clinical judgment – there is an over-emphasis on one component (reviews) over the other (clinical judgment) when it states that systematic reviews are “the building blocks” as opposed to “one of the building blocks ” of evidence-based practice.

On page iv of the draft guideline, it misstates that “[i]n designing the study questions, the EPC consulted several Key Informants who represent the end-users of research,” however it has become abundantly clear within the MS physician and patient community (the “end-users”) that none of the major organizations representing either the treating medical professionals (American Academy of Neurology MS Section, Consortium of Multiple Sclerosis Centers, Medical Partnership 4 MS) or patients (MS Coalition, including the Accelerated Cure Project, Can Do Multiple Sclerosis, Consortium of Multiple Sclerosis Centers, International Organization of Multiple Sclerosis Nurses, Multiple Sclerosis Association of America, Multiple Sclerosis Foundation, National Multiple Sclerosis Society and United Spinal Association) were consulted. This obvious omission has the potential to affect the entire nature of the draft document, and highlights again the deficiencies in the process whereby such information is withheld in the draft document. 

Furthermore, the Technical Expert Panel may be deficient (it is unclear since the identity of the panel is withheld) and this has profound implications in terms of “study questions, design, methodologic approaches, and/or conclusions.” There are two clear examples of this: (1) none of the profession or patient organizations dedicated to MS were asked for recommendations regarding potential members of technical expert panel; and (2) the study question concerns discontinuation of MS disease modifying treatments, while the MS professional organizations have been requesting a comparative effectiveness review on the use (not merely the discontinuation of use) of MS disease-modifying treatments. Taxpayer dollars could have been better spent in reviewing the questions that the “end-users” actually have, which is how to select the correct therapy for an individual patient. Instead an unidentified EPC diverted scarce public resources to a faulty draft document without input from the representative of the professionals who care for MS patients or from the MS patient community. This implies that the “end-users” identified on page iv of the draft guideline are actually exclusively health plans, and not individual taxpayers.

The draft guideline purports to be a “comparative effectiveness review,” however the methods described do not allow for such a review, by systematically ignoring vast amounts of highest quality Class I evidence without adequate justification. Again, this may be as a result of a deficient Technical Expert Panel and Key Informants as the research question and its methodologies were not well thought out or developed.  This is further evidenced by the sheer magnitude of MS professional and patient organizations’ response to the draft document.  There are many biases found throughout the draft document, but they become evident immediately upon reading the title and objectives of the draft document. There are no other “discontinuation” guidelines in the EHC (Effective Health Care Program) database; MS seems to be singled out. In a Nomination Summary Document from 02/14/2012 (topic #0305), the nominator discusses developing a survey to examine the early warning signs of MS. According to the Diagnosis and Treatment of Multiple Sclerosis Nomination Summary Document, “[t]he original nomination discusses development of a survey to identify early warning signs of MS. In order to approach the nomination with a comparative effectiveness framework, it was expanded to a consideration of the comparative effectiveness of diagnostic and treatment interventions for MS.” AHRQ staff conclude that “[w]hile there are many reviews that address a range of issues pertinent to the treatment of MS, there is not a product that pulls together all the information on the treatment of MS. Therefore, treatment of MS will move forward as a systematic review.” Unfortunately, AHRQ chose not to move forward with this much needed systematic review, and instead chose to review when to discontinue treatment for a disease “that can cause significant physical, mental, and emotional disability.The Medical Partnership 4 MS requests an explanation for why taxpayer dollars were diverted from helping to answer an important question towards producing a document aimed at withholding care. Did the question of discontinuation originate with the AHRQ or with the individual EPC?
The deficiencies in the investigators used become apparent early on in the draft document, as the terminology used in the Structured Abstract on page v is blatantly incorrect. The investigators refer to “relapse-remitting MS” throughout the draft document, yet no such term exists. The correct term is actually “relapsing-remitting MS.” While on the surface this may seem to be a slight difference, the consistent misuse of a common term familiar to all those who work in the field of multiple sclerosis (but perhaps not to non-experts) demonstrates the non-expert nature of the EPC and its “experts.” The incorrect term “relapse-remitting MS” is used ten (10) times throughout the draft document, while the correct term “relapsing-remitting MS” is used zero (0) times in the body of the draft document. Meanwhile, the correct term is used eight (8) times in the titles of the included references for the Executive Summary, eighteen (18) times in the main references section, twelve (12) times in the excluded studies, fourteen (14) times in the references to Appendix C and nine (9) times in the references to Appendix D.  These glaring errors in the draft document illustrate the flawed methodology, whereby only “two investigators screened abstracts.”

These basic errors make it difficult to believe (p. 6) that “[i]nitially a panel of key informants comprised of MS researchers, clinicians, consumer advocates, and consumers gave input on the key questions (KQs).” Furthermore, at no time were the key researcher and clinician organizations (American Academy of Neurology MS Section, Consortium of MS Center, Medical Partnership 4 MS) or consumer advocate organization (the eight member organizations of the MS Coalition) included. The method of recruitment of the Key Informants and Technical Expert Panel was not included in the draft document (despite its importance to the methods being used).

As in any scientific inquiry, the methodology used needs to be justified, as altering the methodology has a direct effect on the eventual results and conclusions. It is unclear why the EPC investigators chose to exclude studies of two years duration in favor of studies of 3 years or greater. The overwhelming suspicion among the MS community is that this was done in order to exclude the Class I studies supporting treatment, in favor of studies with lower levels of evidence (and potential for greater bias). The EPC investigators do not adequately justify the methodology chosen, and this is a clear deficiency in the draft document.

The investigators assert in the Results section (pp. v, ES-7 and 16), that “[l]ow-strength evidence suggests long-term all-cause survival is higher for treatment naïve RRMS patients who did not delay starting interferon beta 1b by 2 years and used DMTs for a longer duration than those who started later.” This statement belies the astounding fact reported by the original authors, that “in this long-term follow-up (LTF) study, we ascertained the vital status in 98.4% of the original RCT participants and found that the hazard rate for ‘all-cause’ mortality was reduced by 46.8% and 46.0% in the two groups assigned to active treatment during the RCT, compared with those who received placebo. Moreover, the excessive number of deaths in the placebo-treated cohort was accounted for entirely by deaths due to MS-related causes. The number needed to treat (NNT) to prevent one death was 8.”[ii] Furthermore, the long-term follow-up study was of a superior study for several reasons: “[f]irst, in the MS survival study, the cohorts were randomized at onset and were balanced on all measured baseline covariates. Second, a strict intention-to-treat analysis was used. Third, there was near-complete ascertainment of the cohorts after 21 years (98.4%). Fourth, the inclusion of two cohorts on active treatment permitted an internal replication of the findings. Fifth, the primary outcome of the LTF study (death) is an unambiguously objective endpoint, and it was evaluated independently from every RCT outcome.”

The Background section of both the Executive Summary (p. ES-1) and the main draft document (p. 1) again reveals the lack of expertise of the authors of the draft document, as the terminology used to describe MS subtypes is both incorrect and outdated.  Aside from the incorrect term “relapse-remitting MS,” PRMS does not stand for “primary relapsing MS,” but instead for “progressive-relapsing MS.” The use of PRMS has furthermore been eliminated in the most recent re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS.[iii] The term “Clinically Definite MS” has not been used since the McDonald 2001 criteria. The MS subtypes were revised in 2014 to include clinically isolated syndrome (CIS), RRMS with active and progressive modifiers, and PPMS with active and progressive modifiers.

The following sentence contains multiple errors/omissions:  Currently FDA-approved DMT for RRMS include interferon beta-1a and 1b (some formulations also approved for CIS), glatiramer acetate, mitoxantrone (also approved for SPMS and PRMS), natalizumab, fingolimod, and dimethyl fumarate.” Glatiramer acetate (along with some formulations of beta interferons) is also approved for CIS. Additionally, teriflunomide is approved for relapsing forms of MS (and CIS), but it was not listed. Furthermore, the other medications are generally approved for all “relapsing forms of MS” and not merely RRMS (p. 2, Table 1).  The acronym “DMT” is missing the plural “s.” The frank inaccuracies (and sloppy typographical errors) in the draft document continue with the sentence: “The overview and network analysis were too recent to include the newest approved drugs such as fingolimod or dimethylfumerate.” Again, teriflunomide is excluded (despite it being FDA approved prior to dimethyl fumarate) and dimethyl fumarate is misspelled as “dimethylfumerate.”

The search algorithm used for Key Question 1. MS/Drug Names is incorrect and contains omissions – two of the currently FDA-approved DMTs were excluded in the search algorithm (A-1), namely fingolimod and dimethyl fumarate. Finding errors in the search algorithms used is troubling since the results and conclusions of the draft document’s systematic review rely on the quality of the literature search.

The use of the term “first-line treatment” (pp. ES-2, ES-3, ES-16 and 3) is not used correctly by the EPC authors in that they do not only include beta interferons and glatiramer acetate, since “first-line” is not synonymous with first developed or FDA approved (the term is generally reserved for referring to the DMTs used first rather than after a suboptimal patient response).

The EPC authors misuse a reference for the (mis-)statement that “[u]nfortunately, the efficacy level of MS treatments appears to correlate with the frequency and severity of side effects.”[iv] The authors of the reference were mostly referring to two treatment strategies that have not yet been approved by the FDA. Furthermore, two of the currently available FDA-approved DMTs were only approved after the publication of the reference by Weber et al. Furthermore, natalizumab used in a patient who tests negative for the JC virus is a medication with high efficacy but low frequency and severity of side effects.

The authors of the draft document further demonstrate their unfamiliarity with the clinical aspects of MS by stating that “[p]eople taking natalizumab may take a drug holiday or discontinue use completely if their risk factor increases assessed by a positive test for the anti-JCV antibody status.” This sentence implies that simply taking a “drug holiday” (an outdated concept) or discontinuing therapy is a reasonable option with no consideration given to the risk of the disease process itself. On the contrary, one of the biggest unmet needs in MS therapeutics is the difficult decision of which DMT a patient should be placed on after discontinuing natalizumab for the very reason that MS worsens after natalizumab discontinuation.

The EPC authors, in their hurried attempt (p. 24) to exclude any evidence that doesn’t agree with their preconceived biases, overlooked the significance of a study that demonstrated that “those with three or more relapses in the year prior to natalizumab treatment were twice as likely to experience relapse following natalizumab interruption (p=0.04) compared with those with fewer relapses prior to natalizumab.”[v] Instead, this information should be used to highlight the need to not discontinue DMTs because of the risk of disease recurrence (even when a patient appears stable on therapy).

Many assertions in the draft document are not scientifically rigorous, and are not referenced; for example, no reference is given for the following statement: “Neurologists commonly counsel a woman to discontinue her medications 3 months prior to trying to conceive, although rates of fetal exposure to DMT vary greatly by country.” Discontinuing medications 3 months prior to trying to conceive is not considered standard of care.  In a draft document that is supposed to be evidence-based, it is alarming that declarations are made without any supportive evidence, such as: “DMTs for MS are not intended for life-long use.” Such statements (contradicted by FDA labeling) place the AHRQ at risk by choosing polemic and investigator bias over evidence-based medicine. 

The investigators explain on page ES-3 that they chose to ignore objective MRI data because of a single article from 2008 that suggested a lack of strong evidence (at that time) of correlation between MRI and clinical outcomes,[vi] however the investigators chose to ignore more recent studies, including a study that revolutionized the way clinicians make decisions about switching therapy based on MRI activity.[vii] Even the older lone reference cited by the EPC investigators suggests what we now know to be true: “[m]easures related to brain or spinal cord atrophy together with MR Spectroscopy, Magnetization Transfer Imaging and Diffusion Tensor Imaging may be useful in the future to better monitor disease progression in the late degenerative phase of the condition.” The EPC investigators once again demonstrate that they are stuck in the past and that they have not caught up to the “future.”

The investigators chose to ignore the more pressing question for the MS community of when to switch medications because it would “likely require a review of both short- and long-term research,” and instead the investigators chose to focus on the less pressing question of when to discontinue treatment outright (p. ES-3). No explanation is given other than it would require more work on the part of the investigators – is this not what they are being paid taxpayer dollars to do?

The investigators further demonstrate their bias (p. ES-3, Figure A) when they frame the first question for the conceptual framework of Key Question 1 as “does immunotherapy work?” It is abundantly clear from multiple well-designed Class I trials that immunotherapy works in the treatment of MS (this is universally agreed upon in the medical community, and by regulators around the world).

Shortly after investigating Key Question 1a, the EPC authors note (p. ES-8) that “[n]o studies directly assessed continuing versus discontinuing DMT in comparable populations.”  Instead of then exploring the risks of untreated MS (including relapses, time missed from work, informal care, hospitalizations, disability and, even, death), the EPC investigators ignored strong evidence and instead “turned to literature examining benefits for continuing DMT long-term.” Only two studies were selected that explored the long-term benefit of one class of DMTs, while an additional study that contradicted the investigators preconceived bias was ignored. A cohort of 1,504 RRMS (1,103 interferon-beta-treated and 401 untreated) patients was followed for up to 7 years. Results of this study demonstrate that the “IFNbeta-treated group showed a highly significant reduction in the incidence of SP (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.24-0.58 for time from 1st visit; HR, 0.36, 95% CI, 0.23-0.56 for time from date of birth; p < 0.0001), EDSS score of 4 (HR, 0.70, 95% CI, 0.53-0.94 for time from first visit; HR, 0.69, 95% CI, 0.52-0.93 for time from date of birth; p < 0.02), and EDSS score of 6 (HR, 0.60, 95% CI, 0.38-0.95 for time from first visit; HR, 0.54, 95% CI, 0.34-0.86 for time from date of birth; p < or = 0.03) when compared with untreated patients. SP and EDSS scores of 4 and 6 were reached with significant delays estimated by times from first visit (3.8, 1.7, and 2.2 years) and from date of birth (8.7, 4.6, and 11.7 years) in favor of treated patients. Sensitivity analysis confirmed findings.”[viii]  It is unclear why the EPC investigators chose to overlook this study that demonstrates that “IFN-beta slows progression in relapsing-remitting multiple sclerosis patients” in favor of a study with serious methodological issues that confirmed the EPC investigators’ preconceived biases.

The study referenced in support of the EPC investigators’ DMT-nihilism introduced an important source of selection bias. “Although covariate adjustment was undertaken at time zero, this method does not adjust adequately for subsequent treatment decisions. Every patient who ultimately chose not to receive treatment began this option immediately after becoming eligible. If such a patient deteriorated, however, they may have been treated. Thus, only clinically stable patients would remain untreated whereas treated patients would begin therapy at staggered times after eligibility, depending on their clinical status.”[ix] Thus Table A on page ES-8 is deficient in that it ignores an important study, while at the same time downgrading an important objective trial that demonstrates a reduction in mortality and upgrading a trial that has inherent biases. There are two possible explanations for this: (1) the EPC authors have a preconceived bias as to the outcome of their review; or (2) the EPC investigators are simply not expert enough in the field of MS, and do not understand the body of evidence. Based upon the misuse of common words used in the MS literature and the choice of subject matter (despite a greater need for other questions to be answered), the Medical Partnership 4 MS suspects that both explanations may be valid here.  

Furthermore, on page 20, the EPC investigators discount a study by Bergamaschi et al., which “found that a smaller proportion of patients using DMTs (the vast majority of patients used interferons or glatiramer acetate) converted to SPMS compared to the historical control,”[x] simply because the results did not agree with their biases since they found that “[t]his result is inconsistent with the other two studies.”

On page ES-9, Key Question 1b ignores the important question of harms caused, not by the DMTs themselves, but by the MS disease process. Ignoring the dangers inherent in untreated MS and the advancements that have been witnessed over the past two decades does little to advance the health of Americans.

On pages ES-9 – ES-10, in Table B Harms reported from unique studies included in the analytic set, the EPC authors include both injectable (interferon beta and glatiramer acetate) and an oral medication (the previously ignored teriflunomide), yet on page ES-10, the investigators summarize that “[t]he most commonly reported adverse events were injection site reactions, flu-like symptoms, depression, and headache.” This is an inappropriate lumping together of adverse events from different trials of different DMTs with different routes of administration and different mechanisms of action. For example, teriflunomide cannot possibly cause injection site reactions as it is an oral capsule and not an injection; in addition, glatiramer acetate does not cause flu-like symptoms. It appears that the EPC authors’ over-emphasis on adverse events in Key Question 1b, rather than on the harms inherent with not treating (or discontinuing DMTs), is further evidence of the biased approach taken by the EPC.

In exploring the dangers of discontinuing DMTs, the EPC investigators choose (pp. ES-10 – ES-11 and 26) to ignore important data that refutes their biased hypothesis as “[w]omen who discontinue DMT with the intention of becoming pregnant risk increased relapses between discontinuation and pregnancy.” The excuse given for ignoring such vital information is insufficient as the EPC investigators simply state that: “[g]iven that the studied populations are those who became pregnant, none of the studies capture what happens to women who discontinue DMT but do not become pregnant. Therefore, no research has observed whether such women are at increased risk of relapse.” There is no scientific reason to expect that a woman who discontinues her DMT in order to become pregnant and does become pregnant is qualitatively different than a woman who discontinues her DMT in order to become pregnant but does not become pregnant. Therefore, data surrounding the risk of relapses while discontinuing DMTs for the sake of becoming pregnant should be used in a well-balanced review on the subject of DMT discontinuation.

In the Discussion, the EPC authors (ES-13) assert that “[t]here was sparse information available to address…long-term benefits and harms.” However, the EPC authors themselves admit that in terms of the side effect profile of the DMTs “overall long-term harms were found to be no different than short-term harms.” The benefit of having DMTs with good long-term safety profiles should actually have been interpreted as a reason to not discontinue DMTs in light of the harms inherent in untreated MS – however, the EPC authors elected to ignore this conclusion.

The EPC authors (ES-14) assert that “[f]or the special cases of natalizumab and planned pregnancy discontinuations, evidence was insufficient to answer whether discontinuation is problem-free.” However, as discussed above this assertion is not supported in the literature of discontinuation for pregnancy; in addition there is a scientifically-validated growing body of evidence outlining the dangers of MS activity during the time period after natalizumab discontinuation.[xi]

The EPC investigators make a non-evidence-based leap by stating that [i]n the absence of evidence, providers and patients are left with little to inform their preferences and guide their decisions regarding when to discontinue treatments.” As stated above, it is misleading to state that there is an “absence” of evidence regarding the benefits of DMTs and the harms inherent in the natural history of untreated MS. Additionally, the EPC investigators themselves concede that there is a lack of significant long-term risks in continuing treatment. Providers and patients are then left with a decision between treating MS with DMTs that have good long-term safety and discontinuing DMT use, which is likely dangerous due to the prognosis of untreated MS.   

The EPC investigators ignore important aspects of evidence-based medicine when they state (p. ES-14) that “[w]ithout more solid evidence for the long-term net benefits, or the thresholds at which treatment is no longer effective in preventing disease progression, the decision to discontinue treatment remains preference sensitive.” EBM dictates that individual clinical expertise, and not merely preferences, be used when there is insufficient evidence from systematic research: “The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research ...  External clinical evidence can inform, but can never replace, individual clinical expertise, and it is this expertise that decides whether the external evidence applies to the individual patient at all...”[xii] Furthermore, it is obvious that discontinuation of DMTs is patient driven since patients only require a physician’s prescription to initiate a DMT and not to discontinue it.

The EPC authors make a blatantly incorrect statement unsupported by (and contrary to) EBM in the Issues section (ES-15) when they write that “[w]hether DMTs for CIS patients is effective remains an open question.” There have been multiple studies demonstrating that various DMTs are effective in clinically isolated syndrome (CIS) – these studies have led to the FDA approval of three beta interferons, glatiramer acetate and teriflunomide for CIS. Furthermore, the term “benign” is used seven ties throughout the draft document in reference to MS, yet the US National MS Society (NMSS) Advisory Committee on Clinical Trials made it clear that “The terms “benign” and “malignant” disease are often misused and should be used with caution.”3

In the Future Research section (pp. ES-16 and 49), the EPC authors note that “[a] prospective 10-year observational study based on the United Kingdom’s MS risk sharing scheme is underway to evaluate the effectiveness of the first DMTs, interferon’s and Glatiramer acetate” and that 6 year-data is being analyzed. This data was indeed analyzed and presented at the 2014 joint ACTRIMS-ECTRIMS (Americas Committee for Treatment and Research in Multiple Sclerosis – European Committee for Treatment and Research in Multiple Sclerosis) annual meeting. Palace et al. found that “[a]fter 6 years of follow-up, the observed increase in EDSS for patients with active relapsing remitting (RR) MS was less than the modelled natural history cohort. The observed progression for utility (the primary outcome) was consistent with a relative rate of progression of 0.58 (Markov model) or 0.56 (MLM) which was better than predicted. For EDSS, the relative rates were 0.76 (Markov model) and 0.61 (MLM) respectively. A range of sensitivity analyses examining the potential for various biases such as loss to follow-up continue to show a better outcome than in the untreated cohort.” The researchers concluded that “[t]his is the largest observational study measuring the effect and cost-effectiveness of the IFb preparations and GA, and provides evidence that as a therapeutic group they alter the natural history of RR MS in the real life setting. If sustained over 20 years, the magnitude of the treatment effect observed would be consistent with the pre-defined cost-effectiveness target of £36,000 ($61,000, Є45,000) /QALY.” This new data (from the largest dataset) contradicts the EPC investigators’ assertion that DMTs are ineffective in the long-term. Additionally, the researchers found that the DMTs were even cost effective for patients with secondary-progressive multiple sclerosis. Had the EPC investigators actually been true experts in the field of MS, they would have been aware of this research being presented at the largest scientific MS meeting.

Despite all of the limitations of this draft comparative effectiveness review, the EPC authors pay the least attention to the limitations of their document, and make the Limitations section the shortest portion of their Discussion.

On page v, the EPC investigators conclude that “MS patients and providers have little information to guide decisions to discontinue DMT.“ This demonstrates the EPC authors’ misinterpretation of the large body of literature that demonstrates a beneficial effect of DMTs on patients with MS, the relatively good safety profiles of the DMTs and the risks inherent from the natural history of untreated MS. It is imprecise to state (pp. ES-14 and 47) that “[i]n the absence of evidence, providers and patients are left with little to inform their preferences and guide their decisions regarding when to discontinue treatments.” There is sufficient evidence to support continuing DMTs, while there is insufficient evidence to supporting discontinuing DMTs – this is a crucial distinction as any draft comparative effective review published by the AHRQ may be used in whole (or in part) as a guideline to deny care for vulnerable patient populations (the very people that AHRQ, as an agency of the Department of Health and Human Services, is tasked with protecting).

The Conclusions in the Structured Abstract of the draft document are insufficient in that they do not go far enough to protect patients (and they contradict the AHRQ’s mission to produce evidence to make health care safer, higher quality, more accessible, equitable, and affordable) by making it clear that because of the lack of evidence to support discontinuing therapy, patients should not be discontinued for any other reason than a medical one since there is an unknown risk in doing so (just as we don't stop aspirin for prevention of heart attacks at some arbitrary age). Having people with MS discontinue DMTs based on lack of evidence would ultimately make health care less safe, of lower quality, less accessible, less equitable and less affordable (as it would drive up the cost of disability and relapses from untreated MS). This strengthening of the conclusion is important in order to meet the AHRQ’s mission of working “within the U.S. Department of Health and Human Services and with other partners to make sure that the evidence is understood and used.” The conclusions of the draft document are difficult to understand, and there is a high risk that the draft document will not be used appropriately (and will instead be used as a justification for arbitrary treatment discontinuation).

The Medical Partnership 4 MS recommends that, at a minimum, the Conclusions of the draft document should be strengthened and clarified to: “MS patients and providers have information to guide continuing DMTs, but little information to guide justifications to discontinue DMTs. In the absence of well-designed long-term observational studies that address benefits and harms of discontinuing DMTs, individualized expert clinical judgment should be used. The preferences literature underscores the complexity of the topic and the processes underlying decisionmaking.”

As noted above, there are multiple problems with the draft document on discontinuation of disease-modifying treatments for multiple sclerosis. These deficiencies stem from and include:

1.     The non-expert nature of the EPC, its Key Informants and Technical Expert Panel – this is apparent due to the misuse of basic terminology related to MS, as well as use of outdated concepts.
2.     The non-inclusion of organizations comprising medical professionals involved in MS care (American Academy of Neurology MS Section, Consortium of MS Centers, Medical Partnership 4 MS) and patient-oriented organizations (eight member organizations of the MS Coalition).
3.     Incomplete literature search methodology.
4.     Arbitrary exclusion of Class 1 evidence based on treatment duration.
5.     Unsubstantiated erroneous statements (such as the lack of evidence regarding treating clinically isolated syndrome).
6.     Inclusion of studies that support the preconceived biases of the EPC authors’ and exclusion of evidence that contradicts these biases.  
7.     The exclusion of key evidence from data surrounding discontinuation of natalizumab and surrounding discontinuation for the sake of trying to become pregnant.
8.     Ignoring the inherent risks in untreated MS by minimizing the severity of the disease.
9.     Weakening what could be a very individualized patient-centered conclusion.

Due to the errors, omissions and bias of the EPC investigators, we ask that the draft not be adopted, and instead, we welcome a meeting of the true stakeholders take place to discuss next steps with the AHRQ.

It is our hope that together with AHRQ staff, we can further refine the gaps in knowledge, and then develop a comprehensive plan to answer vital questions for people with MS, including treatment initiation, selection and even discontinuation (if appropriate).

Thank you for the opportunity to comment on the draft document. We look forward to discussing these important issues further. If you have any questions, please contact Daniel Kantor at or 904-834-3007.


Medical Partnership 4 MS
Accelerated Cure Project for MS (ACP)
Can Do Multiple Sclerosis
Consortium of Multiple Sclerosis Centers (CMSC)
International Organization of MS Nurses (IOMSN)
Multiple Sclerosis Association of America (MSAA)
Multiple Sclerosis Foundation (MSF)
Neuroscience Centers of Florida Foundation
Rany Aburashed DO
Enrique Alvarez, MD, PhD
Lilyana Amezcua, MD
Ariel Antezana, MD
Michelle L. Apperson, MD, PhD
Ronald O. Bailey, M.D.
Matthew J. Baker, MD
Daniel S. Bandari, MD
Donald A Barone, DO
Rifaat M. Bashir, MD
Ann D. Bass, M.D.
Jeffrey Bennett, M.D., Ph.D.
Michael E. Batipps, MD, FAAN
Christine M Boutwell, MD
David Brandes, MD
Jonathan Calkwood, MD
John Corboy, MD
Ardith M. Courtney, DO
Shanker Dixit, MD
Jeffrey B English, MD
Edward Fox, MD, PhD
Doug Franklin
S. Mitchell Freedman, MD FAAN
Elliot Frohman, MD
Teresa C Frohman, PA-C
Gloria von Geldern, MD
Barbara Giesser, MD
Myles Goble, MD
Douglas Goodin, MD
Joseph B. Guarnaccia, MD
Mark Gudesblatt, M.D.
June Halper, MSN, APN-C, MSCN, FAAN
Gail Hartley, MSN, NP, MSCN
David Hojnacki MD
Annette M. Howard, MD
Bruce L. Hughes MD
Samuel F. Hunter, M.D., Ph.D.
Brian Hutchinson, PT, MSCS
George J. Hutton, MD
Alan K Jacobs, MD FAAN
Todd J. Janus, Ph.D., M.D., FAAN
Douglas R. Jeffery M.D., Ph.D.
David E. Jones, MD
Daniel Kantor, MD
Bhupendra O. Khatri, M.D.
Ilya Kister, MD
John F Kurtzke MD, FACP, FAAN
Chris Laganke, MD
Neil S. Lava, MD
Elisabeth Lucassen, MD
Tamara Miller, MD
Kirstin M. Nygren, NP
Gabriel Pardo, MD
Jenifer Patterson, APRN, MSCN
James R Piotrowski , PA-C, MS
David Rankine MD
Tony Reder, MD
Marc C. Rice, MD
Emily Riser, MD
Peter Riskind MD PhD
Victor M. Rivera, M.D., FAAN
Derrick Robertson, MD
Stephen J Rosenberg, MD, FAAN
Amy Perrin Ross, APN, MSN, CNRN, MSCN
Richard A. Sater, M.D., Ph.D.
Alan R. Segaloff
Stuart Silverman MD FAAN
James P. Simsarian MD
Derek Smith, MD
Brian Steingo, MD
Leslie J. Tarlow, RN, MSN, GNP-BC, MSCN
Carolyn Taylor, M.D.
Albert B Vasquez M.D.
Stephen G. Vincent, MD, FAAN
Peter B. Wade, MD
Megan R. Weigel, DNP, ARNP-c, MSCN
Bianca Weinstock-Guttman, MD
Catherine A. Weymann, MD
Kathleen M. Wiese, DO
Jerry S. Wolinsky, MD, FAAN, FANA, FAAAS, EASCI
Daniel Wynn, MD FACN FAASM
Robyn G. Young, MD

CC: Robert Kronick, Ph.D., Director, Agency for Healthcare Research and Quality
CC: Yen-pin Chiang Ph.D., Acting Deputy Director, Center for Evidence and Practice Improvement, AHRQ
CC: Stephanie Chang, M.D., M.P.H., Director, EPC Program, Center for Evidence and Practice Improvement, AHRQ
CC: Scientific Resource Center, Portland VA Research Foundation

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