Guiding Principles for Evaluating Vaccines in Joint Health Technology Assessment in the European Union: Preparing for the EU's Regulation on HTA for Vaccines.

OBJECTIVES: The appraisal of vaccines in the European Union (EU) currently involves many different decision-making bodies and processes. The objective of this study was to help inform the development of standardized methodology and vaccine-specific processes for use in the EU Regulation on health technology assessment (HTA). METHODS: Literature reviews and expert consultation were conducted to identify current practices and gaps related to vaccine appraisals and to develop guiding principles for the joint clinical assessment of vaccines. RESULTS: We found that significant variation exists across the EU Member States in the decision-making processes when clinically evaluating vaccines. Three guiding principles consisting of 13 recommendations were developed to help inform the development of decision-making frameworks for the joint clinical assessment of vaccines in the EU: (1) Support the creation of appropriate terminology and measurements for clinical appraisals of vaccines; (2) Develop inclusive, timely, and transparent vaccine appraisal processes to support stronger evidence generation for vaccine decision-making and appraisal; and (3) Improve the collection and interoperability of real-world data, including robust surveillance, to foster evidence generation and support the standardization of vaccine clinical appraisals. CONCLUSIONS: Given the significance of vaccines for public health, there is an urgency to develop standardized and vaccine-specific methodologies and processes for use in the EU joint HTA framework. The proposed guiding principles could support the effective implementation of the EU Regulation on HTA for vaccines and have the potential to ensure consistent, transparent, and timely access to new vaccines in the EU.

Estimated health and economic impact of using high-dose influenza vaccine on respiratory and circulatory plus respiratory hospitalizations of older adults in Australia.

Background: Standard dose influenza vaccine provides moderate protection from infection, but with lower effectiveness among the elderly. High dose and adjuvanted vaccines (HD-TIV and aTIV) were developed to address this. This study aims to estimate the incremental health and economic impact of using HD-TIV (high dose trivalent vaccine) instead of aTIV (adjuvanted trivalent vaccine) on respiratory and circulatory plus respiratory hospitalizations of older people (≥65 years) in Australia. Methods: This is a modelling study comparing predicted hospitalization outcomes in people receiving HD-TIV or aTIV during an average influenza season in Australia. Hospitalization records of Australian adults ≥65 years of age from 01 April to 30 November during 15 influenza seasons (2002-2017 excluding 2009, which was a pandemic) were extracted from the Australian Institute of Health and Welfare [AIHW] and used to calculate hospitalisation rates during an average season. Relative vaccine effectiveness data for aTIV and HD-TIV were used to estimate morbidity burden related to influenza. Results: Between 2002 and 2017, the average respiratory hospitalization rate among older people during influenza season (April-November) was 3,445/100,000 population-seasons, with an average cost of AU$ 7,175 per admission. The average circulatory plus respiratory hospitalization rate among older Australian people during that time was 10,393/100,000 population-seasons, with an average cost of AU$ 7829 per admission. For older Australians, HD-TIV may avert an additional 6,315-9,410 respiratory admissions each year, with an incremental healthcare cost saving of AU$ 15.9-38.2 million per year compared to aTIV. Similar results were also noted for circulatory plus respiratory hospitalizations. Conclusions: From the modelled estimations, HD-TIV was associated with less economic burden and fewer respiratory, and circulatory plus respiratory hospitalizations than aTIV for older Australians.

Cost-effectiveness of high dose versus adjuvanted trivalent influenza vaccines in England and Wales.

AIMS: High dose trivalent influenza vaccine (HD TIV) and adjuvant TIV (aTIV) have been developed specifically for adults aged 65 and older (65+) who are at high risk of life-threatening complications. However, there is a scarcity of evidence comparing the clinical and cost-effectiveness of HD TIV and aTIV. The aim of this study was to determine the cost-effectiveness of HD TIV versus aTIV in the England and Wales 65+ population. METHODS: A cost-utility analysis was conducted using a decision tree with two influenza related outcomes: Laboratory confirmed cases that could result in GP consultation, and hospitalizations that may result in premature mortality. Due to a lack of comparative evidence, the effectiveness of HD TIV versus aTIV was calculated indirectly, based on relative effectiveness estimates for each vaccine versus a common comparator, standard dose (SD) TIV. The primary analysis included hospitalizations explicitly due to influenza/pneumonia. Cost-effectiveness was established for three scenarios applying differing relative effectiveness estimates for aTIV versus SD TIV. Uncertainty was analysed in one-way deterministic sensitivity analyses. A secondary analysis included hospitalizations due to any respiratory illness. RESULTS: The minimum population impact of vaccination with HD TIV rather than aTIV was 13,092 fewer influenza cases, 1,109 fewer influenza related deaths, 4,673 fewer hospitalizations, and 3,245 fewer GP appointments. HD TIV was cost-effective versus aTIV for all three effectiveness scenarios, with incremental cost-effectiveness ratios (ICER) equal to £1,932, £4,181, and £8,767 per quality adjusted life year. Results were consistent across the secondary analysis and deterministic sensitivity analyses. LIMITATIONS: The analysis was limited by a lack of robust and consistent effectiveness data for aTIV. CONCLUSION: HD TIV is cost-effective versus aTIV in people aged 65+ in England and Wales. Use of HD TIV over aTIV could increase clinical benefits and reduce the public health and economic burden of influenza.

Economic evaluation of high-dose inactivated influenza vaccine in adults aged ≥65 years: A systematic literature review.

INTRODUCTION: Due to waning immunity, adults aged ≥65 years are at increased risk of seasonal influenza infection and its complications. Adding to this risk, older adults have reduced responses to influenza vaccines. A high-dose trivalent inactivated influenza vaccine (Fluzone High-Dose, Sanofi Pasteur) (IIV3-HD) was developed to improve protection against influenza in adults aged ≥65 years and has been licensed in the US since 2009 and in Canada since 2015. Post-licensure studies have shown that IIV3-HD is more effective than standard-dose trivalent inactivated influenza vaccine (IIV3-SD) at protecting against influenza infection in this population. Here, we performed a systematic review of economic analyses of IIV3-HD in adults aged ≥65 years. METHODS: On June 9, 2019, using the Ovid search platform, we searched Econlit, Embase, and Ovid MEDLINE® for original studies published in peer-reviewed journals examining the economics or cost-effectiveness of IIV3-HD in adults aged ≥65 years. Two reviewers independently selected studies and assessed their quality. RESULTS: Seven studies were selected, all performed in the US or Canada. Five studies were funded by IIV3-HD manufacturer, and the remaining two by the US National Institute of General Medical Sciences. In all studies, IIV3-HD reduces healthcare resource utilization and is cost-effective or cost-saving compared to IIV3-SD. The main driver is reduced hospitalizations for cardiorespiratory events. CONCLUSION: IIV3-HD is cost-saving or cost-effective versus IIV3-SD in adults aged ≥65 years. Reduced cardiorespiratory complications are an important driver of these economic benefits. A video summary of the article can be accessed via the Supplementary data link at the end of this article.

Cost-effectiveness analysis of the nine-valent HPV vaccine in Italy.

BACKGROUND: In Italy HPV vaccination with the quadrivalent vaccine (Gardasil®) is offered actively and free of charge to girls aged 12 since 2007. A nine-valent vaccine (Gardasil 9®) received the European market authorization in 2015 to protect, with only 2 doses, against around 90% of all HPV positive cancers, over 80% of high-grade precancerous lesions and 90% of genital warts caused by HPV types 6/11. METHODS: A dynamic transmission model simulating the natural history of HPV-infections was calibrated to the Italian setting and used to estimate costs and QALYs associated with vaccination strategies. The analyses compared two strategies with the nine-valent vaccine (cervical cancer screening and vaccination in girls only or vaccination in boys and girls) to four alternative strategies (cervical cancer screening and vaccination with quadrialent vaccine in girls only, in both boys and girls, with bivalent vaccine in girls and screening strategy only). The National Health Service perspective was considered. CONCLUSION: The switch to the nine-valent vaccine in Italy can further reduce the burden associated to cervical cancer and HPV-related diseases and is highly cost-effective. RESULTS: Compared to the current vaccination program with quadrivalent vaccine, the nine-valent vaccine in a programme including girls and boys shows further reductions of 17% in the incidence of cervical cancer, 35 and 14% in anal cancer for males and females, as well as over a million cases of genital warts avoided after 100 years. The new technology is associated with an ICER of 10,463€ per QALY gained in universal vaccination, decreasing to 4483€ when considering the vaccine switch for girls-only.

Systematic review of cost-effectiveness analyses for combinations of prevention strategies against human papillomavirus (HPV) infection: a general trend.

BACKGROUND: Due to the arrival of multi-valent HPV vaccines, it is more and more important to have a better understanding of the relationship between vaccination and screening programmes. This review aimed to: (1) collect published evidence on the cost-effectiveness profile of different HPV prevention strategies and, in particular, those combining vaccination with changes in screening practices; (2) explore the cost-effectiveness of alternative preventive strategies based on screening and vaccination. METHODS: A systematic literature review was conducted in order to identify the relevant studies regarding the cost-effectiveness of prevention strategies against HPV infection. Analysis comparing the modelling approaches between studies was made along with an assessment of the magnitude of impact of several factors on the cost-effectiveness of different screening strategies. RESULTS: A total of 18 papers were quantitatively summarised within the narrative. A high degree of heterogeneity was found in terms of how HPV prevention strategies have been assessed in terms of their economic and epidemiological impact, with variation in screening practice and valence of HPV vaccination found to have large implications in terms of cost-effectiveness. CONCLUSIONS: This review demonstrated synergies between screening and vaccination. New prevention strategies involving multi-valence vaccination, HPV DNA test screening, delayed commencement and frequency of screening could be implemented in the future. Strategies implemented in the future should be chosen with care, and informed knowledge of the potential impact of all possible prevention strategies. Highlighted in this review is the difficulty in assessing multiple strategies. Appropriate modelling techniques will need to be utilised to assess the most cost-effective strategies.

An estimate of the public health impact and cost-effectiveness of universal vaccination with a 9-valent HPV vaccine in Germany.

INTRODUCTION: Since 2007, the German Standing Vaccination Committee recommends HPV vaccination for girls aged 12-17 with a 2- (Cervarix®) or 4-valent (Gardasil®) vaccine. A 9-valent vaccine (Gardasil 9®) recently received a European market authorization in 2015. METHODS: A dynamic transmission model was calibrated to the German setting and used to estimate costs and QALYs associated with vaccination strategies. RESULTS: Compared to the current vaccination program, the 9-valent vaccine extended to boys shows further reductions of 24% in the incidence of cervical cancer, 30% and 14% in anal cancer for males and females, as well as over a million cases of genital warts avoided after 100 years. The new strategy is associated with an ICER of 22,987€ per QALY gained, decreasing to 329€ when considering the vaccine switch for girls-only. CONCLUSION: Universal vaccination with the 9-valent vaccine can yield significant health benefits when compared to the current program.

Public health and economic impact of seasonal influenza vaccination with quadrivalent influenza vaccines compared to trivalent influenza vaccines in Europe.

Influenza B strains represent on average 23% of all circulating strains in Europe and when there is a vaccine mismatch on B strains, additional influenza-related hospitalizations and deaths as well as substantial additional costs are observed. The objective was to estimate the public health and economic impact of seasonal influenza vaccination with quadrivalent influenza vaccines (QIV) compared to trivalent influenza vaccines (TIV) in Europe (EU). Based on data from 5 EU countries (France, Germany, Italy, Spain and UK) during 10 influenza seasons from 2002 to 2013, epidemiological and associated economic outcomes were estimated for each season for the actual scenario where the TIV was used, and for a hypothetical scenario where QIV could have been used instead. By using QIV, this study estimated that for the 5 EU countries, an additional 1.03 million (327.9/100,000 inhabitants) influenza cases, 453,000 (143.9/100,000) general practitioners consultations, 672,000 (213.1/100,000) workdays lost, 24,000 (7.7/100,000) hospitalizations and 10,000 (3.1/100,000) deaths could have been avoided compared to the use of TIV over the 10-seasons-period. This study estimates that QIV can be of economic value since from a societal perspective 15 million Euros would have been saved on general practitioners consultations (14 million Euros from third-party payer perspective), 77 million on hospitalizations (74 million Euros from third-party payer perspective) and 150 million Euros on workdays lost, across the 5 EU countries. In conclusion, the present study estimates that, compared to TIV, QIV may result in a substantial decrease in epidemiological burden and in influenza-related costs.

Cost-effectiveness analysis of a vaccination program for the prevention of herpes zoster and post-herpetic neuralgia in adults aged 50 and over in Germany.

Herpes zoster (HZ; shingles) is a common viral disease that affects the nerves and surrounding skin causing a painful dermatomal rash and leading to debilitating complications such as, mainly, post-herpetic neuralgia (PHN). Currently, there is no effective treatment for HZ and PHN. The objective of this study was to assess the cost-effectiveness of a HZ vaccination program in Germany. An existing Markov Model was adapted to the German healthcare setting to compare a vaccination policy to no vaccination on a lifetime time-horizon, considering 2 scenarios: vaccinating people starting at the age of 50 or at the age of 60 years, from the perspective of the statutory health insurance (SHI) and the societal perspective. According to the perspective, vaccinating 20% of the 60+ German population resulted in 162,713 to 186,732 HZ and 31,657 to 35,793 PHN cases avoided. Corresponding incremental cost-effectiveness ratios (ICER) were 39,306 €/QALY from the SHI perspective and 37,417 €/QALY from a societal perspective. Results for the 50+ German population ranged from 336,468 to 394,575 HZ and from 48,637 to 56,087 PHN cases avoided from the societal perspective. Corresponding ICER were 39,782 €/QALY from a SHI perspective and 32,848 €/QALY from a societal perspective. Sensitivity analyses showed that results are mainly impacted by discount rates, utility values and use of alternative epidemiological data.The model indicated that a HZ vaccination policy in Germany leads to significant public health benefits and could be a cost-effective intervention. The results were robust and consistent with local and international existing literature.

Role of vaccination in the sustainability of healthcare systems.

The use of vaccines to prevent diseases in children, adults, and the elderly results in fewer medical visits, diagnostic tests, treatments, and hospitalisations, which leads to substantial savings in healthcare costs each year in Europe and elsewhere. Vaccines also contribute to reducing resource utilisation by preventing nosocomial infections, such as rotavirus gastroenteritis, which can increase hospital stays by 4-12 days. Vaccination also has an important role in the prevention of cancers with, for example, human papillomavirus or hepatitis B vaccines. Since the financial impact of cancer is high for patients, healthcare systems, and society as a whole, any cases prevented will reduce this impact. Newer vaccines, such as the herpes zoster vaccine, can provide an answer to unmet medical needs by preventing and reducing the severity of shingles and associated post-herpetic neuralgia, which are difficult conditions to treat. Thus, in the context of increasing pressure on healthcare budgets, vaccination can contribute to the sustainability of healthcare systems through reduced and more efficient use of healthcare resources.

Mind the gaps: what's missing from current economic evaluations of universal HPV vaccination?

BACKGROUND: Since the original licensing of human papilloma virus (HPV) vaccination for women, evidence is accumulating of its effectiveness in preventing HPV-related conditions in men, and universal vaccination (vaccinating men and women) is now recommended in some countries. Several models of the cost-effectiveness of universal HPV vaccination have been published, but results have been mixed. This article assesses the extent to which economic studies have captured the range of values associated with universal HPV vaccination, and how this influences estimates of its cost-effectiveness. METHODS: Eight published economic evaluations of universal HPV vaccination were reviewed to identify which of the values associated with universal HPV vaccination were included in each analysis. RESULTS: Studies of the cost-effectiveness of universal HPV vaccination capture only a fraction of the values generated. Most studies focused on impacts on health and health system cost, and only captured these partially. A range of values is excluded from most studies, including impacts on productivity, patient time and costs, carers and family costs, and broader social values such as the right to access treatment. Further, those studies that attempted to capture these values only did so partially. DISCUSSION: Decisions to invest in universal HPV vaccination need to be based on a complete assessment of the value that it generates. This is not provided by existing economic evaluations. Further work is required to understand this value. First, research is required to understand how HPV-related health outcomes impact on society including, for instance, their impact on productivity. Second, consideration should be given to alternative approaches to capture this broader set of values in a manner useful to decisions-makers, such as multi-criteria decision analysis.

Cost-effectiveness of vaccination against herpes zoster and postherpetic neuralgia: a critical review.

OBJECTIVE: The objective of this study was to systematically review cost-effectiveness studies of vaccination against herpes zoster (HZ) and postherpetic neuralgia (PHN). METHODS: We searched MEDLINE and EMBASE databases for eligible studies published prior to November 2013. We extracted information regarding model structure, model input parameters, and study results. We compared the results across studies by projecting the health and economic impacts of vaccinating one million adults over their lifetimes. RESULTS: We identified 15 cost-effectiveness studies performed in North America and Europe. Results ranged from approximately US$10,000 to more than US$100,000 per quality-adjusted life years (QALY) gained. Most studies in Europe concluded that zoster vaccination is likely to be cost-effective. Differences in results among studies are largely due to differing assumptions regarding duration of vaccine protection and a loss in quality of life associated with HZ and to a larger extent, PHN. Moreover, vaccine efficacy against PHN, age at vaccination, and vaccine cost strongly influenced the results in sensitivity analyses. CONCLUSION: Most studies included in this review shows that vaccination against HZ is likely to be cost-effective. Future research addressing key model parameters and cost-effectiveness studies in other parts of the world are needed.

A critical review of cost-effectiveness analyses of vaccinating males against human papillomavirus.

A critical review of cost-effectiveness analyses of HPV vaccination in males was conducted and nine studies were identified in different countries. Due to the heterogeneity among these studies in terms of modeling approach, vaccination strategies, health outcomes considered, assumptions and parameters, limited conclusions can be drawn with regard to the absolute cost-effectiveness. Nevertheless, key drivers were identified. More favorable cost-effectiveness appeared when all HPV-related diseases outcomes were considered, a suboptimal vaccine coverage among girls and/or lower vaccine prices were assumed. There was a general lack of transparency to fully describe the details of the methodological approach of modeling and calibration. Further research should be conducted to generate robust evidence-based data sets (HPV-related diseases epidemiology, costs and quality of life). The best modeling practice for HPV vaccination and how to better capture the true economic value of vaccination beyond cost-effectiveness in a broader policy context need to be investigated.

Economic evaluation of vaccines: specificities and future challenges illustrated by recent European examples.

This study reviews the current challenges in the economic evaluation of vaccines with a focus on European countries. In particular, the type of clinical evidence generally available, the impact of discounting for time preference and the use of modeling to derive valid cost-effectiveness assessments are considered. First, the characteristics of evidence for vaccines are discussed, as well as potential difficulties faced when using evidence-based medicine applied to curative drugs to interpret vaccine evidence. Then, discounting is considered and specific examples illustrating issues with different types of discounting are described, taking HPV as the example. Finally, the need for sometimes complex dynamic models for vaccines is explored, and specific types of models are reviewed, keeping into consideration the adage "complex when needed, straightforward if allowed."

Economic burden of non-cervical cancers attributable to human papillomavirus: a European scoping review.

OBJECTIVE: Human papillomavirus (HPV) has an important role in the aetiology of a range of diseases, including cervical, other anogenital, and head and neck cancers, genital warts and recurrent respiratory papillomatosis. This literature review was conducted to identify the available cost data for non-cervical HPV-related cancers (anal, penile, vulvar, vaginal, head and neck) in Europe and to inform discussion of methodological challenges for future economic research. METHODS: The literature search was conducted using Medline and key words to identify papers published in English or French between 1 January 2000 and 31 December 2011. Abstracts of major conferences were searched to identify relevant information. Structured methods were used to select references that focused on overall disease management for inclusion in the review. RESULTS: A total of 21 references from seven countries (Denmark, France, Germany, Greece, The Netherlands, Portugal, and the UK) were selected, including 11 references relating to head and neck cancers, five to anogenital cancers, and five to more than one HPV-related disease. Non-cervical cancers accounted for a substantial proportion of the economic burden of HPV-related cancers, and this burden was mainly driven by men (∼70%). A wide range of costs were reported for each disease, particularly head and neck cancers, predominantly due to disease complexity and variation in study design. LIMITATIONS: The main limitation of this study was in the search strategy, which was constrained by the key words, the database searched, and the restriction on language (English/French). CONCLUSIONS: Non-cervical cancers attributable to HPV impose a substantial economic burden in Europe, and the burden is greater in men than in women. This review provides useful information for future health-economic studies assessing the impact of HPV vaccination on all HPV-related diseases.

A comparative analysis of the epidemiological impact and disease cost-savings of HPV vaccines in France.

The aim was to compare the epidemiological and economic impact of 16/18 bivalent and 6/11/16/18 quadrivalent HPV vaccination in France, considering differences in licensed outcomes, protection against non-vaccine HPV types and prevention of HPV-6/11-related diseases. The differential impact of the two vaccines was evaluated using a published model adapted to the French setting. The target population was females aged 14-23 y and the time horizon was 100 y. A total of eight different scenarios compared vaccination impact in terms of reduction in HPV-16/18-associated carcinomas (cervical, vulvar, vaginal, anal, penile and head and neck), HPV-6/11-related genital warts and recurrent respiratory papillomatosis, and incremental reduction in cervical cancer due to potential cross-protection. Quadrivalent vaccine was associated with total discounted cost savings ranging from EUR 544-1,020 million vs. EUR 177-538 million with the bivalent vaccination (100-y time horizon). Genital wart prevention thanks to quadrivalent HPV vaccination accounted for EUR 306-380 million savings (37-56% of costs saved). In contrast, the maximal assumed cross-protection against cervical cancer resulted in EUR 13-33 million savings (4%). Prevention of vulvar, vaginal and anal cancers accounted for additional EUR 71-89 million savings (13%). In France, the quadrivalent HPV vaccination would result in significant incremental epidemiological and economic benefits vs. the bivalent vaccination, driven primarily by prevention of genital. The present analysis is the first in the French setting to consider the impact of HPV vaccination on all HPV diseases and non-vaccine types.