Institute for Patient Access & Affordability (IPAA) is a new program division of Patients Rising with the mission to provide patient-powered pathways to help both public and private payers as they make critical coverage decisions for patients with rare and chronic diseases. As scientific innovation advances and evolves, it is imperative that we look beyond the one-size fits all approach to identify ways to promote access and maintain affordability. IPAA evaluates the various frameworks and protocols used to access and demonstrate the value of new treatments to ensure that the patient is kept at the center of these decisions. To support our work, we engage stakeholders to foster realistic, people-centered, solution-oriented discussions to create balanced, truthful and equitable dialogues around health care access and affordability issues.
We appreciate the opportunity to provide our comments on ICER’s September 12th Draft Evidence Report about “Oral Semaglutide for Type 2 Diabetes.” As you know, people with diabetes also often have other related conditions (such as obesity, high blood pressure and high cholesterol), and thus may be taking medicines and other treatments for those conditions – including biopharmaceuticals, devices, surgeries, and lifestyle changes – which can make their overall health care and self-care regimens complicated. We point this out at the beginning of our comments to highlight the importance of communications and collaboration between a patient and their clinical team, and the very personal nature of the process for making individualized treatment decisions. Therefore, we urge ICER to recognize that policy makers need to have people-centered perspectives that focus on treatment and care plans for the person, and not siloed onto specific treatments, diseases or conditions – and that people are much more than the sum of their diseases and health conditions.
Our specific people-focused comments about the draft report are organized below into sections about People-Centered Perspectives; Timing of Report; Individualized Treatment Approaches for Diabetes; Data Uncertainty; Other Analytical and Methodological Concerns; and Additional Points. And within those sections we have identified specific questions or points for ICER to respond to with this symbol ».
The draft report does a good job of describing the complexity of type-2 diabetes, and presents a reasonable although limited overview of the range of possible treatment options. For example, it would be good to note that weight loss for people with T2DM – which may be achieved with “nutrition therapy and physical activity (“lifestyle changes”)”[i] – can help reduce the significance of the disease and lessen a person’s need for medicines.[ii] As good clinicians know, support for such life style changes requires a variety of resources and skills within the care team, such as cognitive behavioral therapy. It has also been proposed that gastric bypass surgery (or similar interventions) may be reasonable treatment options for obese people with diabetes since it may lead to remission or a cure for their diabetes.[iii] We point out these treatment options for people with diabetes and urge ICER to consider and evaluate the full spectrum of treatment options in their analyses – including all the associated cost, benefits, risks, and people-centered factors.
In the report, we believe ICER could use more patient friendly language, such as specifying that “hospitalizations for major cardiovascular disease (CVD)”[iv] means heart attacks and strokes. We note this because the hospitalizations are actually for sequela from the underlying CVD, such as a heart attack or stroke. That is, if someone has stable CVD they would likely not be hospitalized simply because they have CVD. Using those terms for CV events requiring hospitalization is akin to the military using the term “collateral damage” to refer to civilian deaths.
We appreciate ICER noting that costs of medicines are a concern for patients, and citing the CDC’s survey about the impact of those costs for people with diabetes and how it effects their adherence to medications.[v] »Related to that point, it would appropriate for the draft report to note that the July 17, 2019 notice from the IRS that enables high deductible health insurance plans staring in 2020 to cover treatments for diabetes (“Insulin and other glucose lowering agents”) before a person has met their deductible amount.[vi]
In the past, we have commented on ICER’s limited use of focus groups – including its inclusion of information about a focus “group” that only included three people.[vii] In the same vein, we note that the current draft report cites information from a single patient.[viii] Since an anecdote is not data, we continue to urge ICER to work with patient groups on real data collection through responsible methodologies such as well constructed surveys and focus groups.[ix]
Timing of Report
»Because on September 20th the FDA approved oral semaglutide (brand name Rybelsus[x]), and that the price will reportedly be $772 per 30 tablets across all doses,[xi] the report’s text, tables and analyses at a minimum should be updated with that information. However, we believe it would be more appropriate to revise and reissue the draft report with updated information.
Further supporting our rationale for ICER to put forth a revised draft report rather than a final version is that ICER has modeled a variety of scenarios beyond the base case and plans on including a modified societal perspective in a future version of the report.[xii]We read this to mean that ICER is withholding other modeling and analysis. We are particularly troubled that a societal perspective is considered an after-thought to be completed later, or has been done and is being withheld. If ICER simply did not have the time to complete that analysis, that would be another reason why a revised draft report rather than a final report should be issued. »ICER needs to explain those statements in greater detail and justify its decisions for not including such modeling – whether completed or not.
»Because CV events (i.e., Major Adverse Cardiovascular Events or MACEs) is the “Key Measure of Benefit”[xiii] chosen by ICER for the draft report (with HgA1c and renal function considered as “Intermediate Outcomes” of “Clinical Benefit”[xiv]), wouldn’t it be more useful and responsible for ICER to withhold a final report and instead issue an updated draft report after the FDA acts (or not) concerning the indication for CVD, which is expected in early 2020?[xv] We particularly think this is warranted since ICER has stated in its proposal for updating its framework assessment process[xvi] that it will only review and update its reports a year after the date of its final reports – which means that ICER might not update the final report for oral semaglutide until a year after the FDA has acted on the CVD indication. Of course, if ICER were to state that its 12-month timeline for potentially updating reports is only a guidance and that it will update this report after the FDA acts on the CVD indication, that would be a reasonable approach too. (We also note that the Preamble to the draft report ICER leaves itself that option by stating – without a specific timeframe – that it “may revisit its analyses in a formal update to this report in the future.”[xvii])
Individualized Treatment Approaches for Diabetes
»In the section on Clinical Guidelines,[xviii] we are curious why ICER did not mention the 2019 guidance and algorithm from the American Association of Clinical Endocrinologists and the American College of Endocrinology.[xix] We recognize that the AACE/ACE publication may not be as deep and granular an exploration of treatment options for type-2 diabetes as some of the other guidelines cited, but it does present a prioritized treatment approach and algorithm that is consistent with the recommendations from the other sources cited. Since the primary audience for ICER’s work is in the United States, would it not make sense to cite the recommendations from the two leading groups of clinicians for people with diabetes in the U.S.?
»The draft report notes that “oral semaglutide is administered on an empty stomach, which may affect adherence and acceptability”[xx] but does not pair that notion with the similar concept that patients might prefer swallowing a pill once a day rather than a subcutaneous injection once a week – particularly in a population that is likely already taking other oral medications. We note that this concept is raised later in the report: “Oral semaglutide is likely to allow many patients to remain on oral treatment who would otherwise require escalation of therapy using either an injectable GLP-1 receptor agonist or insulin.”[xxi] We also note that an additional advantage of the oral form of semaglutide is that unlike the injection formulation, it does not have to refrigerated prior to initial use,[xxii] which could be a factor for use for people without access to adequate refrigeration. Such adherence factors should be discussed together rather than separated.
There are a variety of ways ICER embraces uncertainty in the draft report, and Patients Rising Now believes ICER should highlight statements where it declares such uncertainties in bold type and declare them up front in the preamble to the report much like the FDA does with Black Box Warnings. And of course, such important caveats should also be prominent in the Conclusions section. For example:
- “The uncertainty of whether oral and injectable formulations of semaglutide have the same effect on key benefits, along with differences in trial lengths, sample size, and enrollment criteria among all included CVOTs raise concerns about the validity of our analysis. We acknowledge these limitations and emphasize the need to interpret the results with caution.”[xxiii]
- “While the similar point estimates for overall MACE for oral and injectable semaglutide provide additional support for this benefit, s concern affected decisions below about how quantitative analyses used for comparative clinical effectiveness and economic modeling were performed.”[xxiv] »In this discussion, ICER should also include perspectives about why validated markers (such as HbA1c) are so important because long-term clinical trials demonstrating clinical outcomes before FDA approval are impractical and unethical since they would result in denial of beneficial treatments for many years. Such delays and unscientific rationale (i.e., demanding final clinical outcomes) runs counter to FDA’s evidence-based standards and the individual and collective interests of patients, and the United States as a society.
- “we urge caution when interpreting these findings as they are highly uncertain.”[xxv]
- “The results were highly uncertain given (1) statistical variance in the model input parameters and risk equations, (2) additional uncertainties from the NMA caused by concerns about whether effect modification could result from differences in the underlying CVOTs, and (3) the relatively limited (compared to the base-case analysis) number of simulations performed for each parameter necessitated by computation time constraints. As with the base-case results, we urge caution when interpreting the findings of the one-way sensitivity analysis.”[xxvi]
- “All of these incremental value estimates are coupled with high levels of uncertainty. This uncertainty is a combination statistical variance from model parameters and additional uncertainty in the NMA results from which MACE benefits for oral semaglutide are derived. Therefore, it is difficult to draw strong conclusions between oral semaglutide and the other add-on treatments.”[xxvii]
»The draft report cites data about increased risk for retinopathy with oral semaglutide, but the FDA approved label states “Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied.”[xxviii]This should be cited and noted in the report, particularly since ICER seems so enamored with projecting long-term outcomes without data.
»What is ICER’s justification for developing and using an unvalidated model, e.g., “To our knowledge, ours is the first and currently only microsimulation model to undertake such a novel approach to predict these long-term events in T2DM.”[xxix]
Other Analytical and Methodological Concerns
»In the Base Case Analysis, Table 4.1 indicates that 33.3% of the population are current smokers. This is a much higher percentage than the overall U.S. adult population (14%) – particularly those over age 64 (8.2%).[xxx] Does ICER have data to indicate that the target population for the draft report’s analysis (i.e., “adults with T2DM with inadequate glycemic control despite current treatment with antihyperglycemic agent(s)”) actually have such a high rate of smoking? That is, is the data source for this base case population appropriately representative of the target population in the U.S.? This is a critical point since smoking is an independent risk factor for vascular disease.
»In the Utilities section of the draft report it is stated that the “annual disutility for daily injection of insulin (for patients who discontinue treatment) and liraglutide based on Boye et al., who used standard gamble interviews of T2DM patients in Scotland to estimate the utility values for injection-related attributes.”[xxxi] Does ICER have any evidence that the utility values derived from interviewing patients in Scotland represent the same utility perspectives as in the United States?
»For the Budget Impact Analysis, it seems that ICER is assuming that oral semaglutide would completely replace other medicines in the other classes.[xxxii] »Please explain how that is any way a realistic assumption – even for patients who are not adequately controlled on their current regimen? »How can ICER assume that other interventions – including non-pharmacological such as lifestyle changes or surgery – would not used by some of those patients, or that they would just continue to have their diabetes suboptimally managed and with inadequate glycemic control?
- »What is the purpose of ICER analyzing and reporting on health plan coverage since it does not seem to factor into its analysis for the rest of the report? Since health plans and insurance companies know their own coverage policies and can benchmark themselves against their peers and competitors, what is the “value” of including that information in the draft report?
- »Similarly, since it is well known to ICER that health plans do not have coverage policies for unapproved compounds (except under their experimental treatment policies and protocols), what is the point of “looking” for such coverage policies – or in the case of oral semaglutide – using the injection form of the same compound as a surrogate even though there is no evidence that coverage policies may translate to the yet to be approved medicine?
- »Why did ICER look for economic models for something that hasn’t been approved and for which there wasn’t a price (until after September 20, 2019), or any sales of utilization data?[xxxiii] If ICER is concerned about using its resources to provide useful information and analyses, searching for things that are known to not exist seems like an extreme waste of time and resources. Please explain the rationale for conducting such pointless activities.
- On page 37 (last sentence of first paragraph under “Adherence and Use of Rescue Medicine”) there seems to be a typo since the description of Table 3.7 and the table’s data seem to contradict each other, i.e., the table indicates a higher rate of rescue medicine use for people taking placebo compared to oral semaglutide in the PIONEER 1 and 8 studies (15.2% v. 1.1-2.3% and 31% v. 15.5-16.5%).
- Because the analysis of the subgroup with moderate renal impairment[xxxiv] had a mean age of 70 years old it would seem appropriate to analyze this group within the context of Medicare as a payer rather than continue to view ICER’s analyses as applying to the entire U.S. health care system, population, and all payers and insurance plans.
Rising is very excited that people with diabetes now have a new treatment
option. However, we are very concerned that ICER’s actions will embolden health
insurance plans to restrict access for patients, increase administrative
barriers for clinicians, and ultimately harm patients and increase costs for
patients and employers in the U.S.
[i] Draft report p. 9
[iv] Draft report p. 9
[v] Draft report p. 9
[vi] IRS NOTICE 2019-45, Additional Preventive Care Benefits Permitted to be Provided by a High Deductible Health Plan Under § 223, https://www.irs.gov/pub/irs-drop/n-19-45.pdf
[vii] ICER Draft Evidence Report ““Esketamine for the Treatment of Treatment-Resistant Depression” March 21, 2019
[viii] Draft report p. 16
[ix] We note that in ICER’s proposal for updating its Value Assessment Framework process that greater work in this area is being considered.
[xii] Draft report p. 54 and p. 66
[xiii] Draft report p. 39
[xiv] Draft report p. 30
[xv] Draft report p. 10
[xvii] Draft report p. iii
[xviii] Section 2.2 of Draft Report pp. 19-20
[xix] AACE/ACE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM (2019) https://www.aace.com/disease-state-resources/diabetes/clinical-practice-guidelines-treatment-algorithms/comprehensive
[xx] Draft report p. 50
[xxi] Draft report p. 76
[xxii] FDA label for Ozempic, Section 16 “How Supplied/Storage and Handling”
[xxiii] Draft report p. 43
[xxiv] Draft report p. 40
[xxv] Draft report p. 66
[xxvi] Draft Report p. 68
[xxvii] Draft report p. 73
[xxviii] FDA label for Rybelsus, Section 5.3 “Diabetic Retinopathy Complications”
[xxix] Draft report p. 72
[xxxi] Draft report p. 62
[xxxii] “We assumed in our analysis of potential budget impact among the prevalent population that oral semaglutide as a potential ADD for switching would replace entirely the market share of drugs in these other classes, represented by sitagliptin (DPP-4 inhibitor), liraglutide (GLP-1 receptor agonist) and empagliflozin (SGLT-2 inhibitor.” Draft report pp. 78-9
[xxxiii] “In our review of the literature, we found no cost-effectiveness model that compared oral semaglutide to other T2DM treatment strategies.” Draft report p. 71
[xxxiv] Draft Report p. 48