Post-Menopausal Quality of Life Claims: Overlooking the Requirements of Normal Science and Fundamental Measurement in ICER'S Cost-Effectiveness Assessment of Fezolinetant for Moderate to Severe Vasomotor Symptoms.

One of the signal failures in health technology assessment is the absence of consideration given, not only to the standards of normal science, but to those of fundamental measurement. A recent evidence report by the Institute for Clinical and Economic Review (ICER) is emblematic of this failure. Based on a simple linear regression model that translates aggregate scores from the ordinal Menopause-specific Quality of Life Questionnaire (MENQOL) to the ordinal EuroQol EQ-5D-5L, ICER has applied these scores to an assumption driven model simulation to produce preferences, QALYs and incremental cost-per-QALY claims for fezolinetant for moderate to severe symptoms associated with menopause. Unfortunately, the attempt to crosswalk multidimensional or multiattribute ordinal scores is mathematically impossible. The 'created' EQ-5D-5L preferences are, as a result, of no interest. The overall result is that the ICER modelled claims for cost-effectiveness fail the required standards for normal science and fundamental measurement. fundamental are impossible. This is unfortunate, although it might be possible to assess certain domains of the MENQOL for their approximation to an interval score with the application of the Rasch Rating Scale Model, this will not support quality of life claims. A preferred approach would be to consider an alternative latent trait for quality of life in menopause, applying Rasch Measurement Theory (RMT), to develop a polytomous instrument that has the required measurement properties. The purpose of this commentary is to point out, as a number of previous commentaries have done, that this framework for creating assumption driven simulated modelled claims has no role in decisions for product assessment, access to formulary and pricing. This commentary expands upon these previous commentaries in placing RMT is the context of a needed paradigm shift to support the evolution of objective knowledge. This is critical if we are to understand, from the individual's perspective, not only an accurate assessment of the burden of menopause but to see this as part of an on-going research program that has to rely on fundamental measurement.

Rasch Measurement and Patient Reported Value Claims: A Primer for Hemophilia.

This commentary proposes that Rasch Measurement Theory (RMT) is an innovative method for assessments of patient-centric therapy response in hemophilia A and B, as they are in other disease states or target patient populations. RMT is a necessary and sufficient approach to moving from ordinal observations to interval measurement, which has arithmetic properties. This applies across the board in hemophilia and other disease states for clinical value claims, patient centric or subjective value claims as well as those for anticipated drug utilization and other medical care resources. The purpose of this commentary is to point out limitations regarding current methods for making claims regarding hemophilia response and to propose a new start in hemophilia studies to identify core claims that meet required measurement standards. This applies to both the development of new patient reported outcome instruments as well as the evaluation of existing instruments, with a focus on polytomous instruments and their sub-domains, to evaluate their possible application as measures that approximate RMT requirements.

Formulary Submissions: Value Claims, Protocols and Outcomes Based Contracting in Rare Disease.

Outcomes based payments contracting is in its infancy. The increased attention being given to rare disease place a premium on the ability to engage with payers to ensure that there is an analytical framework relevant to value claims contracting. Rare disease is not, of course, alone; many other chronic disease states may be suitable candidates and have been over the past 10 years or more. Rare disease, however stands apart: (i) the evidence base at product launch is limited; (ii) the therapy costs are often considered prohibitive; and (iii) the target patient population is small. At the same time, those seeking to implement an evidence-based engagement with health systems to support innovative rare disease interventions face a substantive technology assessment barrier. The focus in health technology assessment on assumption driven modeled cost-effectiveness simulations that support imaginary recommendations for cost-effective pricing and access is, however, an avoidable barrier. In the US, this barrier is the business model of the Institute for Clinical and Economic Review (ICER) and one endorsed by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Rare disease can be better served with other tools at our disposal with a proposed new start analytical framework in health technology assessment. The purpose of this brief note is to make the case that this proposed new start focused on single attribute value claims that meet the standards of normal science and fundamental evidence can not only dispense with the ICER imaginary modeling but, with a new start formulary submission package, integrate value claims with assessment protocols to set the stage for effective outcome-based contracting as the default standard for future payer negotiations.

Evidentiary Standards for Patient-Centered Core Impact (PC-CIS) Value Claims.

Proposals for a patient centered core impact set (PC-CIS) are of little relevance to formulary and health system decisions, let alone patients and providers, unless the elements included in the data set meet the standards of normal science and fundamental measurement. Adhering to these standards will have the effect of focusing on the adequacy of proposed core impact measures, with a filter in place to accept only those that meet the standards not only of the physical sciences but also mainstream economics. and health economics. Fortunately, we are well aware of what the criteria for acceptance and rejection of the core impacts within disease states should be in terms of their required attributes and their relevance for supporting evaluable value claims, notably for patient reported outcomes, Rasch or modern measurement theory. Care must be taken to delineate the core impact elements: separately identifying those that are purely clinical from core patient centric impacts, which is turn should be separated from impacts defined in terms of drug utilization and resource utilization. The purpose of this brief commentary is to set out the required standards for core impact patient-centric value claims and the framework for evaluating those claims. The critical issue for patient-centered core impacts is to recognize the constraints imposed by the standards of fundamental measurement for target patient populations within disease areas; unless these constraints are recognized we will fail. The leads to the role of Rasch or modern measurement theory calibration as the framework for patient centric measures of latent traits or attributes. From these perspectives PC-CIS is premature; until we have agreed standards for measurement for the impact or outcomes for clinical, patient-centric and resource utilization as a core set of disease specific instruments, it seems pointless to push forward to a wider scope when the present evidentiary foundation is so weak.

Concerns with Patient Reported Outcome Measurement and Value Claims for Therapy Response: The Case of Mavacamten and Symptomatic Hypertrophic Cardiomyopathy (SHCM).

Fundamental measurement is the basis for a rational assessment of patient reported outcome (PRO) value claims; both as response to therapy and the submission of credible and evaluable value claims to formulary committees and other health system decision makers. It is important to emphasize the importance of creating interval and ratio scales as opposed to nominal and ordinal scales to support value claims; a recognition that follows from acceptance of conjoint simultaneous measurement and the contribution of Rasch or modern measurement theory (RMT). Failure to appreciate the role of RMT has led thousands of researchers simply to apply numerals to events, inappropriately applying the techniques of classical statistical analysis, with the result that all that is produced are ordinal PRO scores. Instead, we should be aiming for interval and ratio scores based on a comprehensible latent trait and the application of the Rasch model. The purpose of this brief commentary is to review the measurement properties of PRO value claims for mavacamten (Camzyos; Bristol Myers Squibb) in symptomatic hypertrophic cardiomyopathy (SHCM) and to judge whether they have any validity when judged against the requirements of modern measurement theory. The assessment includes both the recent evidence report by the Institute for Clinical and Economic Review (ICER) for mavacamten as well as pivotal randomized trial (RCT) value claims that combine clinical endpoints with PROs that fail the standards of fundamental evidence. These include the Kansas City Cardiomyopathy Questionnaire (KCCQ), the New York Heart Association (NYHA) functional classification and the EuroQuol EQ-5D-5L multiattribute health related quality of life (HRQoL) preference instrument. The review concludes that apart from purely clinical claims based on the various pivotal trials, there are no PRO claims for mavacamten in SHCM that meet the required measurement standards.

Mapping Impossible Utilities: The ICER Report on Tezepelumab for Severe Asthma.

The focus of this commentary is on the attempt to create EQ-5D-3L ordinal preferences from a disease specific asthma questionnaire, the Asthma Quality of Life Questionnaire (AQLQ). The question is whether it is possible from the perspective of fundamental measurement to create a simple linear algorithm to map AQLQ scores to EQ-5D-3L preferences. It is proposed that this is mathematically impossible as the aggregate AQLQ score is ordinal, apart from the fact that the AQLQ is a multiattribute score that lacks construct validity and any pretense to having interval properties. Disallowing the mapped utilities means that the modelling cannot be sustained. It is proposed that the focus should be on single attribute measures of the latent construct "need fulfillment quality of life". These measures would meet the required standards of Rasch Measurement Theory (RMT) applying simultaneous conjoint standards of measurement theory, as well as capturing the patient voice.

Fundamental Measurement: The Need Fulfilment Quality of Life (N-QOL) Measure.

The quality adjusted life year (QALY) has serious problems related to its failure to adhere to measurement theory. If a QALY is to be meaningful, the utility score that translates time spent to an equivalent time spent in so-called perfect health must have ratio properties (i.e., it must support multiplication). Multiattribute utility scores (e.g. those generated by the EQ-5D-5L) fail to meet this standard. The multiattribute instruments produce ordinal scores that lack a true zero and they generate negative values. The manifest deficiencies of multiattribute utility instruments render them unfit, not only as a measure of therapy response but also in generating QALY claims. After 30 years of belief in their use, utilities and QALYs are clearly analytical dead ends. The purpose of this commentary is to demonstrate a coherent way forward in health technology assessment by focusing, not on clinical attributes as surrogates for quality of life, but on measures that are based on a conceptual model describing patient value in terms of need-fulfilment. Building on an extensive, yet often overlooked literature, need-based measures that fit Rasch Measurement Theory criteria are converted from ordinal scores to interval scores to evaluate response to therapy. These measures meet the requirements of single attribute fundamental measurement which is the standard in the physical sciences. It is proposed that a translation from a Rasch interval scale (defined by logits) can be transformed to a bounded ratio scale. Need based Quality of Life (N-QOL) scales bounded by 0 (where no needs are fulfilled) to 1 (where all needs are fulfilled) form such scales. The N-QOL supports the full range of arithmetic operations. Multiattribute utilities and mathematically invalid QALYs can be put to one side as unfortunate historical curiosities in favor of a disease or target population specific N-QOL scale. Such a scale has the required properties to evaluate disease specific response to therapy This can also support N-QOL adjusted life years with a need- fulfillment life year (NALY) metric with ratio properties.

Fundamental Outcome Measurement: Selecting Patient Reported Outcome Instruments and Interpreting the Data they Produce.

Over the past 40 years literally thousands of generic and disease specific patient reported outcome (PRO) instruments have been developed. While most were developed for a specific study and were never used again, there is still the question of how manufacturers and others should select a PRO instrument for a study. These studies may be clinical pivotal trials or observational tracking studies to support therapy response. Formulary committees also need to be able to interpret PRO data to make decisions about whether to accept claims for therapy response. It is possible to argue that the many different approaches to outcome measurement have resulted from the lack of agreed methodologies. However, a more likely explanation is that the authors have failed to apply the axioms of fundamental measurement when creating their measures. The result is a plethora of ordinal PRO instruments that inform little about the impact of interventions. Clinical trials rarely report PRO data. Where they do, analyses are generally restricted to (for example) changes in the experimental group's scores. Comparisons between the treatment and placebo groups or between active groups are infrequently reported, most likely due to the failure of the instrument to show differences or changes in outcome. This is unfortunate as it means no assessment is made of the value that patients gain from the intervention. This commentary is intended to make researchers and formulary committees aware of the issues that need to be addressed when selecting PRO instruments for a study or evaluating publications and claims for therapy response. The latter is crucial as reported data influence the selection of medicines and healthcare products. In the latter case a particular concern is with PRO claims embedded in simulation models.

Peter Rabbit is a Badger in Disguise: Deconstructing the Belief System of the Institute for Clinical and Economic Review in Health Technology Assessment.

The Institute for Clinical and Economic Review (ICER), a Boston-based consulting group, has seen itself as the lead organization in the US for evaluating pharmaceuticals and, at product launch, making recommendations for pricing and access. Previous commentaries in Innovations in Pharmacy have made the case that the ICER analytical framework is nonsensical. It abandons the standards of normal science in favor of inventing evidence through unsupported assertions regarding measurement properties and lifetime assumption driven simulations. It has been labeled pseudoscience. Yet ICER persists in its belief that all preference scales have ratio properties. ICER believes it can disregard these standards, notably in respect of the axioms of fundamental evidence, and continue its technology assessment activities. Challenging a belief system is not undertaken lightly, although in the case of ICER the belief system is built on such shaky foundations that the effort seems almost superfluous. This deeply held belief, shared apparently by the majority of health economists according to ICER, that all preference scores have ratio properties with a true zero, is easily overturned: if it has ratio properties how is it that preferences scores have been known for over 30 years to recognize health states worse than death? In other words, they can have negative preferences. Recognizing this manifest contradiction is important because it brings into relief the wider belief system of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) who share the same mythical certainties. A key issue is one of cultural relativity: can we accept with equanimity the parallel existence of two belief systems in health technology assessment when one is clearly nonsense? The answer proposed here is clearly no; although unfortunately the blowback by ICER and ISPOR will ensure the survival at least in the near term of their unfortunate meme.

Let a Thousand Models Bloom: ICER Analytics Opens the Floodgates to Cloud Pseudoscience.

It has been noted on numerous occasions that modeled claims for cost-effectiveness, if driven by assumption for the lifetime of a hypothetical patient population, can be easily 'gamed' to create a required claim. These marketing exercises to support product entry are all too common in the literature. The institute for Clinical and Economic Review (ICER) in its launch of the ICER Analytics platform has provided a framework to support precisely these activities. Following the mainstream methodology in health technology assessment, the ICER Analytics platform facilitates the creation of approximate information to support formulary decisions. This is an odd development because it undercuts ICERs belief that it is the key arbiter in health technology assessment in the US, setting the stage for pricing and access recommendations. With the release of the ICER Analytics platform, others can now customize the 'backbone' ICER model in a disease area (i.e., change assumptions) to develop alternative and competing value assessments and 'fair' price claims. The problem is, of course, that without a reference point, there is no basis for comparing modeled claims other than through challenging assumptions. Indeed, ICER has made this easy by reducing barriers to lifetime model building so that manufacturers and others can create competing (and confusing) claims within, literally, a few minutes. ICER will then become one of a multitude of competing voices for the attention of formulary committees and other health decision makers; letting a thousand imaginary models bloom where no model can be judged on the basis of credible, empirically evaluable and replicable product claims.

Medicaid Formulary Decisions and the Institute for Clinical and Economic Review: Abandoning Pseudoscience in Imaginary Pharmaceutical Pricing Claims.

Medicaid formulary committees and other gatekeepers face a difficult task. On the one hand they can utilize technical expertise in evaluating the real world evidence for clinical, quality of life and resource utilization claims for competing products while on the other hand they may be asked to assess claims built by simulation models for pricing and product access. A common option has been to take modeled claims from third parties such as the Institute for Clinical and Economic Review (ICER) at face value without challenging the model structure, its assumptions and its incremental cost-per-QALY claims set against competing products or the existing standard of care. Unfortunately, from the available evidence, it seems clear that many formulary assessment groups, last but not least those for whom the ICER modeling claims are targeted, have little if any appreciation of the limitations of ICER modeling. There are two substantive issues: (i) a failure to appreciate the limitations imposed by the standards of normal science for credible, empirically evaluable and replicable product claims and (ii) an understanding of limitations imposed by the axioms of fundamental measurement. In the latter case, a failure to recognize that the quality adjusted life year (QALY) is an impossible mathematical construct (hence the I-QALY). To these limitations should be added the potential for constructing competing imaginary claims. Surprisingly, ICER has provided the ideal opportunity to construct competing claims with the launch in late 2020 of the ICER Analytics cloud platform. Formulary committees and other health decision makers should be aware that claims based on the ICER Analytics platform together with competing lifetime modelled claims all fail the standards of normal science. Factoring these into formulary decisions is not only misguided but may have unintended consequences for pricing and access that may disadvantage significantly patients and caregivers. We have spent too much time debating the merits or otherwise of the I-QALY for targeted patient groups with the parties failing to recognize that the focus on simulated cost-per-I-QALY value assessments is a mathematical folly; I-QALY claims are a chimera. The I-QALY, at long last, should be abandoned together with modelled lifetime simulations. Medicaid formulary decision makes should rethink the required evidence base for formulary decisions and negotiations. Care should be taken to revisit previous negotiations where ICER recommendations have been utilized to support pricing and access.

Abandoning Eugenics and the QALY.

Should decision making in health care, notably in respect of the allocation of resources between individuals and disease states, rest on notions of the burden of disease and denial of care as assessed by societal evaluations or on the extent to which the need of patients and caregivers is fulfilled. The prospect of the denial of health care, for those deemed 'unworthy' has a long history in the eugenics movement. Many have assumed that this 'utilitarian aberration' has long been discredited. Unfortunately, once the question of the allocation of limited health care resources is considered it reasserts itself; manifested in the creation of health state preferences and states worse than death, and application of the cost-per-QALY calculus driving claims for pricing and access. In the US, this focus on cost-per-QALY claims is most closely associated with the Institute for Clinical and Economic Review (ICER) with its regular clinical assessments and modelled imaginary simulations supporting recommendations which, in many if not most cases, give support to the denial of care. The purpose of this commentary is to point to the unfortunate similarities between 'eugenic' decision making and the application of thresholds in burden of illness cost-per-QALY exercises. If we are to finally rid ourselves of a 'eugenic' approach to health care resource allocation, then we must abandon preferences and the QALY calculus.

Supping with the Devil: Belief and the Imaginary World of Multiple Myeloma Therapies Invented by the Institute for Clinical and Economic Review.

Previous commentaries in Innovations in Pharmacy and other peer reviewed journals have made the case that the analytical framework, if that is not too strong a term, to support pricing and access recommendations endorsed by the Institute for Clinical and Economic Review (ICER) fails to meet the standards of normal science. By any criteria the ICER analysis is best described as pseudoscience; it fails the demarcation test between biological evolution and intelligent design. Like intelligent design it has its believers; a meme for all seasons. ICER is fully aware of the fact that it fails these standards, yet perseveres. It justifies its cost-per-QALY framework by maintaining3, through unsubstantiated assertions, that it meets standards for scientific credibility; it denies the possibility of negative values and utilities which undercut completely the construction of QALYs. This is nonsense: not only does the ICER framework fail those standards, to include axioms of fundamental measurement, but also a simple rule of logic in basing its models on assumptions. ICER dogmatic adherence to simulation modeling is evidence in its latest report on multiple myeloma. The report is a charade; but unfortunately not one that is rejected by Bristol-Myer Squibb, GlaxoSmithKline, Sanofi and Amgen. Their responses to the draft evidence report points to their acceptance of imaginary simulation constructs to drive pricing decisions. Whether this reflects their unqualified acceptance of the imaginary simulation modelling to create evidence or a failure to appreciate the standards of normal science is unclear. Certainly, in this case they fail to recognize the devastating impact of believing in the use of the EQ-5D-5L preferences to create imaginary or I-QALYs. The question raised in this commentary is whether the willingness to accept the ICER analytical framework reflects a belief in the role of creating evidence, ICER style, or a willingness to accept ICER imaginary conclusions as the easy way out in negotiating prices with insurers and other payers. Accepting ICER imaginary constructs is an analytical dead end that will stifle the discovery of new facts. The question is: so what?

A Critical Examination of Simulation Pricing and Access Recommendations for Atopic Dermatitis.

It has been demonstrated conclusively that value and utility preference scores have only ordinal properties. This means, as has been pointed out on numerous occasions, that the quality adjusted life year (QALY) is a mathematically impossible construct. The implications are profound: Some 30 years of health technology assessment is called into question due to a failure to recognize the well-documented limitations imposed by the axioms of fundamental measurement. The purpose of this commentary is provide a critical examination of this practice in recommendations for atopic dermatitis.

A Critical Examination for the Pricing of Eculizumab and Efgartigimod in Myasthenia Gravis.

The purpose of this commentary is to focus on the downside of assumption-driven simulation modeling, the potential creation of a multitude of competing models, the mathematically impossible quality adjusted life year (QALY) and the failure to observe the axioms of fundamental measurement in mapping ordinal EQ-5D-5L preferences from the ordinal Quantitative Myasthenia Gravis (QMG) score. A second aspect of this commentary is to propose standards that should be set for the creation and evaluation of value claims in health technology assessment, in particular need fulfillment quality of life (QoL), that meet the demarcation test to distinguish science from non-science. The result is that the present ICER pricing claims for eculizumab and efgartigimod in myasthenia gravis should not be applied without consideration of more relevant evidence.

Measurement, modeling and QALYs.

Over the past 30 years, a mainstay of health technology assessment has been the creation of modeled incremental cost-per-quality adjusted life year (QALY) claims. These are intended to inform resource allocation decisions. Unfortunately, the reliance on the construction of QALYs from generic utility scales is misplaced. Those advocating QALY-based lifetime modeled claims fail to appreciate the limitations placed on these constructs by the axioms of fundamental measurement. Utility scales, such as those created by the EQ-5D-3L instrument, are nothing more than multidimensional, ordinal scales. Such scales cannot support basic arithmetic operations. Interval scales can support addition and subtraction; ratio scales the further operations of multiplication and division. Those who advocate the construction of QALYs fail to appreciate that such an operation is only possible if the utility scale is unidimensional and has ratio properties with a true zero. The utility measures available do not meet these requirements. As we cannot produce meaningful utility values, the QALY is an invalid construct. Consequently, cost-per-incremental QALY claims are impossible to sustain and the application of cost-per QALY thresholds meaningless. As utility is a latent, unidimensional variable, the best a measure of utility could achieve would be unidimensionality and interval scaling properties. Where such measures are available, they could support claims for response to therapy. Consequently, there would be no need to continue constructing imaginary lifetime value assessment frameworks. Admitting that the QALY is a fatally flawed construct means rejecting 30 years of cost-per-QALY models.

The National Pharmaceutical Council: Endorsing the Construction of Imaginary Worlds in Health Technology Assessment.

All too often, organizations embrace standards for health technology assessment that fail to meet those of normal science. A value assessment framework has been endorsed that is patently in the realm of pseudoscience. If a value assessment framework is to be accepted, then claims for the value of competing products must be credible, evaluable and replicable. If not, for example, when the assessment relies on the construction of an imaginary lifetime incremental cost-per-quality-adjusted-life-year (QALY) world, then that assessment should be rejected. Such an assessment would fail one of the central roles of normal science: the discovery of new facts through an ongoing process of conjecture and refutation where provisional claims can be continually challenged. It is no good defending an endorsement of a value framework that fails expected standards on the grounds that it has been endorsed by professional groups and reflects decades of development. This is intellectually lazy. If this is the case, then the scientific revolution of the 17th century need not have happened. The purpose of this commentary is to consider the recommended standards for health technology assessment of the National Pharmaceutical Council (NPC), with particular reference to proposed methodological standards in value assessment and the commitment to mathematically impossible QALYs.