Costs and effectiveness of extended vaccination strategies against pertussis and pneumococcal disease

Omdat het Nederlandse Rijksvaccinatieprogramma al intensief is en de gezondheidszorg kampt met gelimiteerde budgetten, zijn de mogelijkheden voor opname van nieuwe vaccins in het Rijksvaccinatieprogramma beperkt. Naast vele andere factoren, hebben doelmatigheidsuitkomsten een groot effect op de beslissing om een vaccin op te nemen in het Rijksvaccinatieprogramma.In het eerste gedeelte van dit proefschrift ligt de focus op de (kosten-) effectiviteit van pneumokokkenvaccinatie.Het blijkt dat er grote verschillen zijn in de geobserveerde epidemiologie na de introductie van het vaccin in Amerika en Europa. In Europa werden er minder pneumokokken gevallen voorkomen in ongevaccineerde individuen (‘herd immunity’) terwijl er meer ziekte werd waargenomen veroorzaakt door serotypen waartegen het vaccin geen bescherming biedt (serotypevervanging). Dit had tot gevolg dat de kosteneffectiviteit van het destijds gebruikte 7-valente pneumokokkenvaccin minder gunstig was dan eerder voorspeld. Meer valente pneumokokkenvaccins hebben een grotere kans om te worden beschouwd als kosteneffectief omdat deze waarschijnlijk meer directe en herd immunity effecten bieden terwijl de kans op serotypevervanging kleiner is. Als gevolg van deze potentiele herd immunity zal het vaccineren van andere (risico-) groepen potentieel minder gunstig worden. Zo blijkt uit een economisch model dat het vaccineren van risicogroepen in Engeland waarschijnlijk niet als kosteneffectief kan worden beschouwd tenzij het vaccin ook bescherming biedt tegen niet-invasieve pneumonie. Dit laatste wordt momenteel onderzocht in een grote Nederlandse klinische trial.Het tweede gedeelte van dit proefschrift verkent de impact van de uitbreiding van het huidige pertussis vaccinatie programma naar adolescenten en volwassenen. Gegeven de complexiteit van de pertussis transmissie, was het nodig een dynamisch transmissie model te ontwikkelen. Dit model suggereert dat de meest kosteneffectieve leeftijd om een extra booster te introduceren rond de 12 jaar is. Het beoogde beschermende effect voor (gedeeltelijk) ongevaccineerde zuigelingen bleek echter minimaal te zijn.Gezien de dynamiek van infectieziekten zijn soms complexe methoden nodig om de impact van nieuwe vaccinatieprogramma’s te voorspellen. Het uitbreiden van het huidige pneumokokken–en pertussis vaccinatieprogramma biedt de mogelijkheid om de morbiditeit en mortaliteit te verminderen en de ziektegerelateerde kosten te verlagen.A crowded vaccination schedule and restrained health–care budgets limit the uptake of new vaccines into the Dutch national immunization programs (NIP). Next to many other factors, costeffectiveness considerations highly influence the decision whether to introduce vaccines into Dutch NIP.The first part of this thesis focuses on the (cost-) effectiveness of pneumococcal vaccination. It is shown that there are large differences in the observed disease epidemiology after implementation of paediatric pneumococcal immunization programs between the USA and Europe. In Europe, less cases of pneumococcal disease were avoided in unvaccinated individuals (herd effects) than in theUSA, while significant replacement was observed in Europe with strains not included in the vaccine.As a consequence, the 7-valent pneumococcal vaccine, which was previously used in the Dutch NIP, was less cost-effective as predicted beforehand. More valent pneumococcal vaccines are more likely to be considered cost-effective as more direct and herd effects and less serotype replacement effects are expected. These potential herd effects reduce the cost-effectiveness of elderly and adult (risk) groups vaccination in time. In particular, a modelling study showed that vaccinating risk groups in England was unlikely to be considered cost-effective in the base-case analysis unless the vaccine would also offer protection against non–bacteraemic pneumonia. Evidence on whether the latter occurs is awaited from a large Dutch clinical trial.The second part of the thesis explores the impact of extending the childhood pertussis vaccination programme to adolescents and adults. Given the nature of the problem, the development of a complex population dynamical model was required. The developed dynamic model showed that the most (cost-) effective age for the introduction of an additional booster is around 12 years. Nevertheless, this strategy only offered limited indirect protection to the (partly)unvaccinated infants with potentially most serious disease which might be considered the primary aim of extended pertussis vaccination.In conclusion, the dynamics of infectious diseases makes it challenging to predict the impact of new vaccination programs. Extending the vaccination programs against pneumococcal disease and pertussis offers the possibility to prevent morbidity and mortality and decrease the economic burden of disease for society

Huge impact of assumptions on indirect effects on the cost-effectiveness of routine infant vaccination with 7-valent conjugate vaccine (Prevnar (R))

Several recently published European cost-effectiveness studies on the 7-valent pneumococcal conjugate vaccine (PCV-7: Prevnar (R)) have included net-indirect vaccine benefits for non-vaccine protected groups into their studies, which might be too optimistic an approach given recent data. Net-indirect effects result from herd protection minus serotype replacement effects. In this study we analyze the impact of net-indirect effects in non-vaccine protected groups of 5 years of age and older with updated assumptions regarding epidemiologic data and health care unit costs. Without net-indirect benefits for non-vaccine protected groups included the cost-effectiveness ratio is estimated at (sic)72,360 per QALY. In order to obtain cost-effectiveness ratios below the threshold of (sic)50,000 per QALY - which is in the middle of the range that is often referred to in the Netherlands - the net-indirect protective effect should at least be 16% of which has been observed in the USA after the introduction of PCV-7. (C) 2010 Elsevier Ltd. All rights reserved

Possible role of cost-effectiveness of HPV vaccination within the decision context on inclusion of HPV in the country-specific national immunization programs

Background: Vaccination against HPV presents a new primary prevention strategy against cervical cancer and is now being introduced in countries all over Europe. Health-economic modelling plays an increasingly important role in the decision making process when introducing new health-care technologies into national programmes. This study compares the economic evaluations used by European countries in the decision making process about the introduction of HPV vaccination in European countries and evaluate the role of these evaluations in this decision making process. Method: Publicly available reports from official government advisory and regulatory bodies were obtained and analysed in terms of their perspective, discount rate, time horizon, type of mathematical model, assumptions made regarding the vaccine and the current screening practice, sensitivity analysis, and outcome. Results: Health-economic studies were found for nine European countries. All analysed in the base-case analysis the cost-effectiveness of vaccination of girls around the age of 12 year in addition to a cervical carcinoma screening program. Both static and dynamic models were used and especially assumptions regarding cost data varied widely among included studies. Estimated incremental cost-effectiveness ratios varied from 11, 400 to 64, 000 per life-year gained in the base cases. Results were most sensitive to the choice of discount rate, vaccine costs and duration of protection after vaccination. Conclusion: We show that cost-effectiveness results cannot be transferred among European countries due to large variations in parameter assumptions. In those countries that undertook an economic evaluation health-economic analyses seem to have played an important role in the decision-making process surrounding the potential introduction of HPV vaccination

The Effect of the Drug Life Cycle Price on Cost-Effectiveness:Case Studies Using Real-World Pricing Data

Objectives: Cost-effectiveness analyses (CEAs) generally assume constant drug prices throughout the model time horizon, yet it is known that prices are not constant, often with price decreases near loss of exclusivity (LOE). This study explores the impact of using dynamic drug-specific prices on the incremental cost-effectiveness ratio (ICER) using selected reproduced case studies. Methods: Case studies were selected following explicit criteria to reflect a variety of drug characteristics. For each drug, a published CEA model was identified, replicated, and modified with dynamic real-world pricing data, to compare ICERs based on constant drug prices with estimates obtained when including drug life cycle pricing. The impact of dynamic real-world pricing—inclusive LOE—was analyzed using a single patient cohort and multiple cohorts over time. Results: Fluvastatin, alendronic acid + colecalciferol combination therapy, letrozole and clopidogrel were selected as case studies. Inclusion of real-world pricing data compared with applying constant prices reduced the ICER in a single-cohort setting up to 43%. In the multicohort analyses, further reductions of the ICERs were observed of up to 113%. The ICERs were sensitive to the period of drug usage relative to the models’ time horizons, the relative proportions of drug costs in the overall treatment costs, and timing of LOE compared with the cost year of the original analysis. Conclusions: Assuming dynamic drug prices may lead to more representative ICER estimates. Future CEAs for drugs could account for predicted and disaggregated life cycle price developments based on retrospective data

Economic evaluation of apixaban for the prevention of stroke in non-valvular atrial fibrillation in the Netherlands

BACKGROUND: Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban is a novel oral anticoagulant associated with significantly lower hazard rates for stroke, major bleedings and treatment discontinuations, compared to VKAs.OBJECTIVE: To estimate the cost-effectiveness of apixaban compared to VKAs in non-valvular AF patients in the Netherlands.METHODS: Previously published lifetime Markov model using efficacy data from the ARISTOTLE and the AVERROES trial was modified to reflect the use of oral anticoagulants in the Netherlands. Dutch specific costs, baseline population stroke risk and coagulation monitoring levels were incorporated. Univariate, probabilistic sensitivity and scenario analyses on the impact of different coagulation monitoring levels were performed on the incremental cost-effectiveness ratio (ICER).RESULTS: Treatment with apixaban compared to VKAs resulted in an ICER of €10,576 per quality adjusted life year (QALY). Those findings correspond with lower number of strokes and bleedings associated with the use of apixaban compared to VKAs. Univariate sensitivity analyses revealed model sensitivity to the absolute stroke risk with apixaban and treatment discontinuations risks with apixaban and VKAs. The probability that apixaban is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 68%. Results of the scenario analyses on the impact of different coagulation monitoring levels were quite robust.CONCLUSIONS: In patients with non-valvular AF, apixaban is likely to be a cost-effective alternative to VKAs in the Netherlands.</p

Assessing the value of orphan drugs using conventional cost-effectiveness analysis:Is it fit for purpose?

Conventional cost-effectiveness analysis-i.e., assessing pharmaceuticals through a cost per quality-adjusted life year (QALY) framework-originated from a societal commitment to maximize population health given limited resources. This "extra-welfarist" approach has produced pricing and reimbursement systems that are not well- aligned with the unique considerations of orphan drugs. This framework has been slow to evolve along with our increased understanding of the impact of rare diseases, which in turn has complicated the assessment of orphan drugs meant to treat rare diseases. Herein, we (i) discuss the limitations of conventional cost-effectiveness analysis as applied to assessing access to, as well as the pricing and reimbursement of, orphan drugs, (ii) critically appraise alternative and supplemental approaches, and (iii) offer insights on plausible steps forward

The Impact of Patent Expiry on Drug Prices:A Systematic Literature Review

OBJECTIVE: The aim of this study was to evaluate the impact of patent expiry on drug prices by means of a systematic literature review. METHODS: A systematic literature search was performed in PubMed to identify all published literature on the impact of patent expiration on drug prices. Additional literature was identified using a less distinct syntax in Google Scholar and EconLit. Data extraction followed a standardized assessment form containing the domains study type, study aim, reported outcomes, number of drugs and drug classes assessed, and originators or generics assessed. RESULTS: The 16 identified studies that assessed impact of patent expiry on drug prices showed that price developments after patent expiration varied between countries. The included studies assessed price developments for the USA, Canada, Australia, the UK, the Netherlands, Germany and France, Spain, Italy, Norway, Sweden and Denmark. The number of drugs included within different studies ranged between 1 and 219. The identified studies indicated that drug prices decreased significantly after patent expiry with drug price ratios ranging from 6.6 to 66% 1-5 years after patent expiry. CONCLUSION: Drug prices decrease significantly after patent expiry. The extent of this price reduction varied greatly between products and countries. For this reason, country-specific analyses on price developments after patent expiry should be used when these are considered in decision making. Future research should be dedicated to gathering more country-specific data to reduce the uncertainty with regard to price developments

The impact of patent expiry on drug prices:insights from the Dutch market

Background: Currently literature on the impact of patent expiry on drug prices is lacking. Objective: To determine the impact of patent expiration and generic entry on drug prices in the Netherlands. Methods: Prescription and price data from 1999 up to and including December 2016 were collected from two national databases. The overall price ratio of drugs prices up to 48 months after patent expiration was compared to the price in the month before expiry. Sub-analyses were performed to provide insights in generic uptake, length of market exclusivity and price development for originators and generics separately. Results: In total 250 drugs faced patent expiration during the study period. Forty-eight months after patent expiration the median price ratio decreased to 0.59 (IQR = 0.23-0.86) compared to the month prior patent expiry. Major differences in price developments were observed depending on the level of revenue prior to patent expiration and the time of patent expiration with ratios ranging from 0.08 (IQR = 0.07-0.16) to 0.81 (IQR = 0.62-0.97). Prior to patent expiry, the price decreased by 2.3% annually while having market exclusivity for 11.3 years on average. Conclusion: This study showed that the median drug price after patent expiration decreased by 41% after 4 years. The results of this study can be used to provide more reliable estimates on drug prices over its lifecycle and can be implemented in economic evaluations to inform the cost-effectiveness and long-term budget impact of new drugs