DMT Discontinuation Review Stirs MS Research Community
The U.S. Agency for Healthcare Research and Quality (AHRQ) recently released a draft review on the evidence on discontinuation of disease-modifying therapies. Shocked by the apparent lack of expertise in the first draft, MS researchers and advocacy groups sent in a wave of comments chastising the AHRQ for the perceived shoddiness of the report.
A draft review of the evidence surrounding discontinuation of disease-modifying therapies (DMTs) has sparked a firestorm within the MS research community.
The draft, released in October 2014 by the U.S. Agency for Healthcare Research and Quality (AHRQ), remained open for comment for the standard four weeks. During that time, the MS research community appeared to unite to express its collective disapproval of the study.
The extensive AHRQ review, titled “Discontinuation of Disease-Modifying Treatment for Multiple Sclerosis,” is 126 pages long and lists nearly 150 references. Its authors, whose names the agency has withheld, examined only long-term studies (longer than three years) related to two key questions: “What are the consequences of discontinuing disease-modifying treatments in adult patients?” and “What are individual values, beliefs, and preferences regarding discontinuing disease-modifying treatments?”
The review concluded that meager information exists to guide patients and their physicians in making decisions about discontinuing DMTs. The authors stated that there’s little evidence suggesting long-term harms are any greater than short-term harms for patients taking DMTs. Similarly, they stated that there’s little evidence supporting long-term benefits from DMTs for patients with relapsing-remitting MS (RRMS).
“It galvanized the MS community”
Despite the ostensibly neutral tone of the review, the MS research community reacted quickly and forcefully.
By the November 10 deadline, the National Multiple Sclerosis Society, Medical Partnership 4 Multiple Sclerosis (MP4MS), the Multiple Sclerosis Coalition, and several other patient-centered and researcher-centered organizations submitted highly critical comments. Their main concerns centered on the potential for healthcare providers and patients to misinterpret the document as justification to go off of treatment when they should not. The commenters were also concerned that insurance companies would use the document to guide their decisions about which medications to cover, and for how long.
“It galvanized the MS community in a way that’s never been galvanized before. We’ve never had such a unified response,” Daniel Kantor, M.D., of MP4MS said in an interview with MSDF. “It’s scary that we need a near-crisis to bring us together.”
The MP4MS letter was highly critical of the study design. Kantor and his fellow signatories suspected that the authors involved in conducting the study were not experts, citing the fact that his group as well as the MS Coalition, the National MS Society, and others were not approached to aid in this study.
Leadership within the Evidence-based Practice Centers (EPC)—the branch of the AHRQ that develops these reviews—appears to have been taken aback by the vehement response. Stephanie Chang, M.D., M.P.H., director of the EPC, expressed surprise at the response from the MS community.
“A lot of [the MP4MS] concerns seemed to be about the process, about which we make every effort to be very open and transparent,” Chang said in an interview with MSDF.
She said the EPC began the research when some people submitted questions to the AHRQ asking that a review look into early diagnosis and clinical signs of MS. The AHRQ then consulted a panel of end-point users of medicine, such as physicians and patients, to see what research should be done in this area.
“We had a stakeholder group that represents people from patients, physicians, and various MS groups,” Chang said. “They together weighed in on the fact that a review of the evidence on discontinuation of therapy would be of interest and had not been addressed by any other review.”
“They leave out a lot of good data”
In addition to questions about the genesis of the study, MP4MS criticized the trials the EPC chose to include in its review and, more importantly, the ones they didn’t include. “They leave out a lot of good data,” said David Jones, M.D., of the University of Virginia. “Any study that was 3 years or less was excluded, and—because of cost—most good studies are 2 to 3 years. The studies that were left had a high risk of bias.” Jones was also a signatory on the MP4MS response.
“It seems like the authors had a conclusion in mind and rejected evidence that didn’t fit with that,” Kantor said.
When MSDF asked about this concern, EPC Task Order Officer Suchitra Iyer, Ph.D., defended the study, saying, “Because the EPC was interested in long-term patient-centered health outcomes and not just short-term outcomes, EPC chose to look at long-duration studies.”
Chang clarified that the document is not intended as a clinical guideline, and that everything about the way the study was conducted was in line with standard operating procedure for the AHRQ, including redacting the names of the authors and key informants in the draft. She said that once the draft is finalized in the spring of 2015, all the names of those involved in the study will be published along with all the comments received during the four-week comment period.
“The EPC is not recommending that patients should discontinue disease-modifying therapies,” Chang said. “The report does not make clinical recommendations.” But instead, she said, it is a review of the evidence.
“It’s not that anyone is saying anything bad, but I think it’s very easy for people to make the wrong assumption that the absence of positive data is the same as negative data, which is what’s happening in this paper. We shouldn’t confuse those two things,” said Rosalind Kalb, Ph.D., vice president of clinical care at the National MS Society, in an interview with MSDF.
“Too easy to be misused or misconstrued”
“It’s just too easy for the paper to be misused or misconstrued as evidence that continuing treatment isn’t helpful,” Kalb continued. “We just don’t know yet. We should be just saying we don’t know this. They say it, it’s embedded in the paper, but the structure of the paper and the title of the paper don’t go along with that conclusion.”
The question of taking people with MS off DMTs often comes up once they enter the progressive phase of the disease. According to Jonathan Carter, M.D., of the Mayo Clinic in Arizona, secondary progressive MS comes with many nuances that are difficult to navigate when making therapeutic decisions. Some patients continue to have relapses and disease activity, while others have low activity.
Carter told MSDF about another situation that occurred in 2013. A seeming lack of understanding of the nuances of progressive MS stirred up similar concerns when the American Academy of Neurology published a list titled “Five Things Physicians and Patients Should Question.” Number four on that list stated that patients in progressive phases of multiple sclerosis should not be given glatiramer acetate or interferon beta because they do not protect against disability and are therefore not cost-effective. Many in the MS community were worried that this list would influence patients against using DMTs and insurance companies against covering them, Carter said.
Carter, who was not a signatory on any of the comments submitted to the AHRQ, told MSDF, “I understand the concern people would have because this [draft] is a government document purporting that this will help develop policy and reimbursement decisions. That always kind of raises a red flag.”
He said that the document also didn’t address his questions as a neurologist. The major question for him is, what are the road signs in a patient’s disease course that suggest that it would be safe to take him or her off therapy?
“They are not able to find any studies because I don’t think any exist of a randomized, placebo-controlled withdrawal of therapy in people who have been on MS therapies for a long period of time,” Carter said. He noted that one abstract was presented at the American Academy of Neurology 2014 annual meeting in Philadelphia, PA, that outlined a prospective study looking at the discontinuation of DMTs in people with progressive MS (Birnbaum, 2014).
All parties agree that more work must be done in this area. AHRQ’s Iyer noted that one of the strengths of the report may be that it underlines the lack of information in this area and hence will inspire more research: “Our report highlights research gaps, and funding agencies can use it to set their research agenda.”
At the end of her interview with MSDF, the AHRQ’s Chang stressed that the EPC takes comments very seriously and will carefully consider all the feedback received on this draft document.
Key open questions
- What research is needed to better answer questions surrounding discontinuation of DMTs?
- How likely is it that this document, if adopted in its present form, will have the far-reaching consequences feared by some groups?
- How does this AHRQ study stack up against others?
Disclosures and sources of funding
MSDF’s parent organization, the Accelerated Cure Project, submitted its own comment suggesting that its clinical research program, OPT-UP (Optimizing Treatment, Understanding Progression), may help answer questions surrounding the discontinuation of disease-modifying therapies.
MP4MS as an organization receives no financial support from pharmaceutical companies. However, Kantor does receive compensation from Acorda, Avanir, Biogen, Genzyme, Novartis, and Questcor.
Carter is a member of a safety and monitoring committee sponsored by EMD Serono.
Jones has received compensation for consulting with Novartis, Genzyme, and Biogen, the latter two through an institutional contract. Jones is also about to start a research project with Biogen, for which he will be the primary investigator.