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MP4MS
|
Medical Partnership 4 MS
221 Stellar Ct.
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
epc@ahrq.hhs.gov
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
info@MP4MS.com or 904-834-3007.
Sincerely,
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.
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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