Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

Health technology assessment (HTA) aims to be a systematic, transparent, unbiased synthesis of clinical efficacy, safety, and value of medical products (MPs) to help policymakers, payers, clinicians, and industry to make informed decisions. The evidence available for HTA has gaps-impeding timely prediction of the individual long-term effect in real clinical practice. Also, appraisal of an MP needs cross-stakeholder communication and engagement. Both aspects may benefit from extended use of modeling and simulation. Modeling is used in HTA for data-synthesis and health-economic projections. In parallel, regulatory consideration of model informed drug development (MIDD) has brought attention to mechanistic modeling techniques that could in fact be relevant for HTA. The ability to extrapolate and generate personalized predictions renders the mechanistic MIDD approaches suitable to support translation between clinical trial data into real-world evidence. In this perspective, we therefore discuss concrete examples of how mechanistic models could address HTA-related questions. We shed light on different stakeholder's contributions and needs in the appraisal phase and suggest how mechanistic modeling strategies and reporting can contribute to this effort. There are still barriers dissecting the HTA space and the clinical development space with regard to modeling: lack of an adapted model validation framework for decision-making process, inconsistent and unclear support by stakeholders, limited generalizable use cases, and absence of appropriate incentives. To address this challenge, we suggest to intensify the collaboration between competent authorities, drug developers and modelers with the aim to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.

Estimates of epidemiology, mortality and disease burden associated with progressive fibrosing interstitial lung disease in France (the PROGRESS study).

BACKGROUND: There is a paucity of data on the epidemiology, survival estimates and healthcare resource utilisation and associated costs of patients with progressive fibrosing interstitial lung disease (PF-ILD) in France. An algorithm for extracting claims data was developed to indirectly identify and describe patients with PF-ILD in the French national administrative healthcare database. METHODS: The French healthcare database, the Système National des Données de Santé (SNDS), includes data related to ambulatory care, hospitalisations and death for 98.8% of the population. In this study, algorithms based on age, diagnosis and healthcare consumption were created to identify adult patients with PF-ILD other than idiopathic pulmonary fibrosis between 2010 and 2017. Incidence, prevalence, survival estimates, clinical features and healthcare resource usage and costs were described among patients with PF-ILD. RESULTS: We identified a total of 14,413 patients with PF-ILD. Almost half of them (48.1%) were female and the mean (± standard deviation) age was 68.4 (± 15.0) years. Between 2010 and 2017, the estimated incidence of PF-ILD ranged from 4.0 to 4.7/100,000 person-years and the estimated prevalence from 6.6 to 19.4/100,000 persons. The main diagnostic categories represented were exposure-related ILD other than hypersensitivity pneumonitis (n = 3486; 24.2%), idiopathic interstitial pneumonia (n = 3113; 21.6%) and rheumatoid arthritis-associated ILD (n = 2521; 17.5%). Median overall survival using Kaplan-Meier estimation was 3.7 years from the start of progression. During the study, 95.2% of patients had ≥ 1 hospitalisation for respiratory care and 34.3% were hospitalised in an intensive care unit. The median (interquartile range) total specific cost per patient during the follow-up period was €25,613 (10,622-54,287) and the median annual cost per patient was €18,362 (6856-52,026), of which €11,784 (3003-42,097) was related to hospitalisations. Limitations included the retrospective design and identification of cases through an algorithm in the absence of chest high-resolution computed tomography scans and pulmonary function tests. CONCLUSIONS: This large, real-world, longitudinal study provides important insights into the characteristics, epidemiology and healthcare resource utilisation and costs associated with PF-ILD in France using a comprehensive and exhaustive database, and provides vital evidence that PF-ILD represents a high burden on both patients and healthcare services. Trial registration ClinicalTrials.gov, NCT03858842. ISRCTN, ISRCTN12345678. Registered 3 January 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03858842.

Assessment and non-clinical impact of medical devices.

Medical devices (MDs) cover a wide variety of products. They accompany changes in medical practice in step with technology innovations. Innovations in the field of MDs can improve the conditions of use of health technology and/or modify the organisation of care beyond the strict diagnostic or therapeutic benefit for the patients. However, these non purely clinical criteria seem to be only rarely documented or taken into account in the assessment of MDs during reimbursement decisions at national level or for formulary listing by hospitals even though multidimensional models for the assessment of health technologies have been developed that take into account the views of all stakeholders in the healthcare system In this article, after summarising the background concerning the assessment of health technologies in France, a definition of non-clinical criteria for the assessment of MDs is proposed and a decision tree for the assessment of MDs is described. Future lines of approach are proposed as a conclusion.

Better defining target populations for drugs with a view to reimbursement.

Reimbursement of drugs by public or private insurance systems is increasingly problematic, including in supposedly "rich" countries. There is an international consensus to consider the benefit of a Health technology assessment to clarify decisions on reimbursement by the collectivity, and this includes taking account of the target population of the new drug. The authors debate about the urgent need of a better quantification of the target population, which must include a qualitative description of this target population and a scientific extrapolation of the target population, which is certainly the most challenging problem.

The public health benefit of medicines: how it has been assessed in France? The principles and results of five years' experience.

Health technology assessment seeks to inform health policy- and decision-makers by promoting use of current best evidence and by addressing country specific factors, such as local context and values. In France, public health benefit (PHB) is one of the criteria used to inform decisions on the reimbursement of medicines. This article describes the methodological framework and the results after five years of assessment of PHB, by the French National Authority for Health. The semi-quantitative method used includes three dimensions that are: (1) the ability of a drug to improve the population's health status, (2) the drug's adequacy to cover public health needs, and; (3) the impact of the drug on the healthcare system. From 2005 to 2010, the PHB of 530 drugs was estimated, and 72% were assessed as having no PHB. The PHB was "low" for 88% of drugs expected to have a PHB, "medium" for 10%, and was considered to be "high" in only one case. The results of this experience show that it is feasible to assess the public health impact of drugs. But the high level of uncertainties at the time of a drug's first appraisal limits the assessment, which obviously has to be completed by reappraisal with post-marketing studies.

A cohort study of therapeutic prescriptions after the end of phytotherapy drug reimbursement by French Social Security.

PURPOSE: The reimbursement of phytotherapy drugs for the treatment of mild anxiety and insomnia ended in March 2006 in France. The aim of this study is to investigate the short-term impact of stopping phytotherapy reimbursement. METHODS: We monitored the prescriptions of 27,422 patients who received hypnotic and sedative phytotherapy drug treatment at least once in the 12 months preceding the end of reimbursement and made contact with their prescribing physician at least once in the following 12 months. A control cohort was recruited from patients fulfilling the same inclusion criteria in the 24 months before de-reimbursement and their prescriptions in the following 12 months were monitored. The impact of the end of reimbursement is estimated comparing prescription switches in these cohorts. RESULTS: Before the end of reimbursement, 7684 (28%) patients being prescribed delisted phytotherapy drugs had the relevant drug marketing authorization approval (DMAA) indications. Co-prescriptions of hypnotic and sedative drugs concerned 40% of patients. Of the 4646 DMAA patients exclusively prescribed phytotherapy, 640 (14%) switched to hypnotic or sedative drugs only after the end of reimbursement, 3266 (70%) stopped all treatments and 740 (16%) carried on with a non-reimbursed phytotherapy prescription. When compared to the control cohort, patients exposed to de-reimbursement were more likely to switch to psychotropic drugs (OR = 1.46). CONCLUSIONS: Ending the reimbursement of common drugs on the basis of insufficient evidence regarding their effectiveness or the low level of severity of their target pathologies should be accompanied by information or advice to prescribing health care actors.

Benchmarking clinical management of spinal and non-spinal disorders using quality of life: results from the EPI3-LASER survey in primary care.

Concerns have been raised regarding sub-optimal utilization of analgesics and psychotropic drugs in the treatment of patients with chronic musculoskeletal disorders (MSDs) and their associated co-morbidities. The objective of this study was to describe drug prescriptions for the management of spinal and non-spinal MSDs contrasted against a standardized measure of quality of life. A representative population sample of 1,756 MSDs patients [38.5% with spinal disorder (SD) and 61.5% with non-spinal MSDs (NS-MSD)] was drawn from the EPI3-LASER survey of 825 general practitioners (GPs) in France. Physicians recorded their diagnoses and prescriptions on that day. Patients provided information on socio-demographics, lifestyle and quality of life using the Short Form 12 (SF-12) questionnaire. Chronicity of MSDs was defined as more than 12 weeks duration of the current episode. Chronic SD and NS-MSD patients were prescribed less analgesics and non-steroidal anti-inflammatory drugs than their non-chronic counterpart [odds ratios (OR) and 95% confidence intervals (CI), respectively: 0.4, 0.2-0.7 and 0.5, 0.3-0.6]. They also had more anxio-depressive co-morbidities reported by their physicians (SD: 16.1 vs.7.4%; NS-MSD: 21.6 vs. 9.5%) who prescribed more antidepressants and anxiolytics with a difference that was statistically significant only for spinal disorder patients (OR, 95% CI: 2.0, 1.1-3.6). Psychotropic drugs were more often prescribed in patients in the lower quartile of SF-12 mental score and prescriptions of analgesics in the lower quartile of SF-12 physical score (P < 0.001). In conclusion, anxiety and depressive disorders were commonly reported by GPs among chronic MSD patients. Their prescriptions of psychotropic and analgesic drugs were consistent with patients' self-rated mental and physical health.

How to best define target populations of medicines in view of their coverage by the national health insurance scheme?

The target population of a medicine may include different populations that may partially overlap including the population that has been evaluated in the clinical trials, the population for which the medicine provides an actual benefit (SMR), that for which the drug provides an improvement of the actual benefit (ASMR), etc. The definition of the target population in both qualitative and quantitative terms has key public health and economic implications. Recommendations are made to shed light on the definitions, to clarify the requests of the public decision makers and to improve the methods and the sources allowing the quantification of target populations.

SCORE should be preferred to Framingham to predict cardiovascular death in French population.

BACKGROUND: Numerous studies have examined the validity of available scores to predict the absolute cardiovascular risk. DESIGN: We developed a virtual population based on data representative of the French population and compared the performances of the two most popular risk equations to predict cardiovascular death: Framingham and SCORE. METHODS: A population was built based on official French demographic statistics and summarized data from representative observational studies. The 10-year coronary and cardiovascular death risk and their ratio were computed for each individual by SCORE and Framingham equations. The resulting rates were compared with those derived from national vital statistics. RESULTS: Framingham overestimated French coronary deaths by 2.8 in men and 1.9 in women, and cardiovascular deaths by 1.5 in men and 1.3 in women. SCORE overestimated coronary death by 1.6 in men and 1.7 in women, and underestimated cardiovascular death by 0.94 in men and 0.85 in women. Our results revealed an exaggerated representation of coronary among cardiovascular death predicted by Framingham, with coronary death exceeding cardiovascular death in some individual profiles. Sensitivity analyses gave some insights to explain the internal inconsistency of the Framingham equations. CONCLUSION: Evidence is that SCORE should be preferred to Framingham to predict cardiovascular death risk in French population. This discrepancy between prediction scores is likely to be observed in other populations. To improve the validation of risk equations, specific guidelines should be issued to harmonize the outcomes definition across epidemiologic studies. Prediction models should be calibrated for risk differences in the space and time dimensions.

How to anticipate the assessment of the public health benefit of new medicines?

The Public Health Benefit (PHB) of new medicines is a recent and French-specific criterion (October 1999 decree) which is often only partially documented in the transparency files due to a lack of timely information. At the time of the first reimbursement application for a new medicine to the "Transparency Committee", the file is exclusively based on data from randomised clinical trials. These data are generated from a global clinical development plan which was designed a long time before the new medicine's submission for reimbursement. And this plan does not systematically provide the data needed to assess the PHB. Thus, one easily understands the difficulty to anticipate and document this recent French criterion. In France, the PHB is both one of the necessary criteria for the reimbursement submission and an indicator for the national health policy management. Its assessment also helps to identify the needs and objectives of the post-registration studies (nowadays in the scope of responsibilities of the "Drug Economics Committee"). The assessment of the PHB criterion is carried through after the marketing authorization process and is an addition to it. To understand how to anticipate the assessment of the new medicines' PHB, one needs to consider how it differs from the preliminary step of the marketing authorization process. Whereas the evaluation for marketing authorization seeks to determine if the new medicine could be useful in a specific indication, the PHB assessment aims at quantifying the therapeutic benefit in a population, taking into account the reference treatments in this population. A new medicine receives a marketing authorization based on the data of the registration file which provides information on the clinical benefit of the new medicine in the populations of the trials and in the context of the trials. On the other side, the PHB looks at the effects of the new medicine at the scale of the general population, in real practice. The PHB components of a new medicine at first submission are the expected response of this new medicine to a public health need, the expected benefit on the health status of the population and ultimately the expected impact on the health care system. The benefit of a new medicine on the health status of a population is based on public health criteria which can be morbi-mortality or quality of life criteria. However, few registration files contain these public health criteria from the beginning and the predictive value of the surrogate criteria used in the trials is not always precisely assessed. It is, thus, difficult to quantify the expected benefit on these public health criteria. Moreover, the data that enable to quantify the new medicine's effects according to the various characteristics of the target population, are rarely available. Similarly, the French population epidemiological data related to the indication of the new medicine are often not available at the time of the assessment. Therefore it is difficult to evaluate the expected number of events that could be avoided if the new medicine reached the market. The authors suggest to adapt the clinical development plan for a better documentation of the PHB. They specifically recommend to integrate to the judgment criteria (endpoints) of the trials, criteria that are relevant in terms of public health, and to check for a good heterogeneity of the trial populations. They also suggest to start early enough collecting reliable national epidemiological data and the necessary elements for the assessment of the transposability of the trial results to the French population (ability to target the patients to be treated, adaptation of the healthcare system...). About the epidemiological data, the authors consider that the needs are covered in various ways depending on the diseases. To meet the needs of evaluation of the new medicines' target populations in specific indications, they recommend to use ad hoc studies as much as needed. In addition, epidemiological studies designed for market purpose with an acceptable methodology should not be systematically rejected but deserve to be presented. To be able to assess the importance of the expected theoretical benefit of a new medicine in a population, the authors underline the necessity to have access to study results with criteria related to this objective. They suggest to first define and list the criteria by disease. Regarding the representativity of the populations, it comes out that it would be advisable, but unrealistic to include in trials a population 100% representative of the population to be treated. Therefore the effect of the new medicine must be modelised (the "effect model") to be evaluated in the general population. Yet to obtain a reliable effect model, the study population must be sufficiently heterogeneous, which legitimates the demand to ensure a good population heterogeneity at the time of decision-making about trials methodology. When the criteria assessed during the development plan does not correspond to the PHB criteria, the only way to evaluate the number of events related to the PHB criterion is, again, to use modelisation. However, modelisation is only possible when the scientific literature has established a reliable correlation between the two types of criteria. In this case, the new model should be applied to a French target population to assess the expected benefit. As a conclusion, the possibilities to estimate the expected benefit of a new medicine on the health status of a specific population are currently limited. These limitations are regrettable because such an estimate is feasible without disrupting the development plans. The authors' general recommendations to update the development plans seem especially appropriate as the additions should not only be beneficial to France but to all the health authorities who would wish to assess the expected benefit of a new medicine on their territories. Anticipating the lack of clinical and epidemiological data and the lack of data that enable to evaluate the transposability of the trials results to real clinical practice is a sine qua none condition to improve the PHB assessment. The anticipation of these needs should be planned early enough by the pharmaceutical companies which could in this purpose meet the health authorities and the heads of the French public health policy in a consultation.Finally, because of the PHB's universal dimension, it is suggested that the necessary actions and publications be initiated so that the PHB can be acknowledged at the European level.