Search

Objectives: The aim of the study was to assess the reimbursement policy for orphan drugs (ODs) in selected European countries in relation to the availability and impact of clinical evidence, health technology assessment (HTA) procedures and reimbursement decision-making. Materials and Methods: A list of authorized ODs was extracted from a web-based registry of the European Medicines Agency, including information on active substance, Anatomical Therapeutic Chemical (ATC) classification code, and therapeutic area. A country-based questionnaire survey was conducted between September 2022 and September 2023 among selected experts from 12 European countries. A descriptive and statistical analysis was performed to identify correlations between country characteristic, HTA procedures, drug indication and positive recommendations or reimbursement decisions for ODs. Results: Safety assessment for ODs was mandatory in 10 countries, while it was optional in one country (Italy) and not required in one country (Iceland). Efficacy assessment for ODs was mandatory in 11 countries and not required in one country (Iceland). The impact of safety and efficacy assessment on reimbursement decisions was rated as high in 10 countries and as low in one country (Germany). Dedicated OD legislation and policies were reported in seven countries. In two countries (Belgium, Iceland), the HTA was not mandatory, and in one country (Germany), it only had an informative function. A positive recommendation (from an HTA agency or advisory body) guaranteed reimbursement in four countries, while a negative recommendation excluded reimbursement only in one country (Iceland). The proportion of reimbursed ODs ranged from 23.5% in Iceland to 86% in Germany (p < 0.001). ODs with ATC code L represented the largest group of medicines (n = 49). They were also very frequently reimbursed ODs in the countries studied, with a mean of 61.8% (p < 0.001). Conclusion: European countries differ in terms of the impact of clinical issues and additional clinical aspects on the reimbursement policy for ODs. Reimbursement decisions were affected by OD-specific legislation, policies, and EMA authorization status. HTA dossiers and procedures significantly influenced reimbursement decisions, although some ODs were reimbursed regardless of the positive or negative recommendations. ATC codes were significantly correlated with reimbursement status and positive recommendation. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to characterize the reimbursement policy for orphan drugs (ODs) in Central and Eastern European (CEE) countries in relation to the availability and impact of clinical evidence, health technology assessment (HTA) procedure, selected economic indicators, and the drug type according to indications. Materials and methods: A list of authorized medicines with orphan designation and information about active substance, Anatomical Therapeutic Chemical (ATC) classification, and therapeutic area was extracted from the web-based register of the European Medicines Agency (EMA). A country-based questionnaire survey was performed between September 2021 and January 2022 in a group of selected experts from nine CEE countries (an invitation was sent to 11 countries). A descriptive and statistical analysis was conducted to determine statistical significance, correlations, between the drug or country characteristic and the positive recommendation or reimbursement of ODs. Results: The proportion of reimbursed orphan drugs differed between countries, ranging from 17.7% in Estonia to 49.6% in Hungary (p < 0.001). The odds that ODs were reimbursed were reduced in countries with a "strong" level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), the presence of other additional specific clinical aspects (e.g., genomic data) considered in the reimbursement decision (p < 0.001) and mandatory (without exception) safety assessments (p=0.004). The probability that ODs were reimbursed was increased in countries with a "moderate" level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), when reimbursement decisions are dependent on the EMA registration status and orphan drug designation (p < 0.001), the presence of the "positive HTA recommendation guarantees reimbursement" policy (p < 0.001), higher GDP per inhabitant (p=0.003), and higher healthcare expenditure (p < 0.001). Conclusion: We found that there are differences among CEE countries in the reimbursement of orphan drugs, and we identified aspects that may influence these differences. Safety, efficacy, and specific clinical aspect issues significantly influenced reimbursement decisions. Antineoplastic and immunomodulating agents drugs were the largest group of ODs and increased the chance of getting a positive recommendation. The higher GDP per inhabitant and healthcare expenditures per inhabitant were positively linked to the chance that an OD receives reimbursement. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to characterize the reimbursement policy for orphan drugs (ODs) in Central and Eastern European (CEE) countries in relation to the availability and impact of clinical evidence, health technology assessment (HTA) procedure, selected economic indicators, and the drug type according to indications.Materials and methods: A list of authorized medicines with orphan designation and information about active substance, Anatomical Therapeutic Chemical (ATC) classification, and therapeutic area was extracted from the web-based register of the European Medicines Agency (EMA). A country-based questionnaire survey was performed between September 2021 and January 2022 in a group of selected experts from nine CEE countries (an invitation was sent to 11 countries). A descriptive and statistical analysis was conducted to determine statistical significance, correlations, between the drug or country characteristic and the positive recommendation or reimbursement of ODs.Results: The proportion of reimbursed orphan drugs differed between countries, ranging from 17.7% in Estonia to 49.6% in Hungary (p < 0.001). The odds that ODs were reimbursed were reduced in countries with a “strong” level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), the presence of other additional specific clinical aspects (e.g., genomic data) considered in the reimbursement decision (p < 0.001) and mandatory (without exception) safety assessments (p=0.004). The probability that ODs were reimbursed was increased in countries with a “moderate” level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), when reimbursement decisions are dependent on the EMA registration status and orphan drug designation (p < 0.001), the presence of the “positive HTA recommendation guarantees reimbursement” policy (p < 0.001), higher GDP per inhabitant (p=0.003), and higher healthcare expenditure (p < 0.001).Conclusion: We found that there are differences among CEE countries in the reimbursement of orphan drugs, and we identified aspects that may influence these differences. Safety, efficacy, and specific clinical aspect issues significantly influenced reimbursement decisions. Antineoplastic and immunomodulating agents drugs were the largest group of ODs and increased the chance of getting a positive recommendation. The higher GDP per inhabitant and healthcare expenditures per inhabitant were positively linked to the chance that an OD receives reimbursement.

BackgroundEvaluating and integrating digital health technologies is a critical component of a national healthcare ecosystem in the 2020s and is expected to even increase in significance.DesignThe paper gives an overview of international practices on public financing and health technology assessment of digital health technologies (DHTs) in five European Union (EU) countries and outlines recommendations for country-level action that relevant stakeholders can consider in order to support uptake of digital health solutions in Hungary. A scoping review was carried out to identify and gather country-specific classifications and international practices on the financing DHTs in five pioneering EU countries: Germany, France, Belgium, the United Kingdom and Finland.ResultsSeveral frameworks have been developed for DHTs, however there is no single, unified framework or method for classification, evaluation, and financing of digital health technologies in European context. European countries apply different taxonomy, use different assessment domains and regulations for the reimbursement of DHTs. The Working Group of the Hungarian Health Economic Society recommends eight specific points for stakeholders, importantly taking active role in shaping common clinical evidence standards and technical quality criteria across in order for common standards to be developed in the European Union single market.ConclusionSpecificities of national healthcare contexts must be taken into account in decisions to allocate public funds to certain therapies rather than others.

In India, there is a renewed emphasis on Universal Health Coverage (UHC). Alongside this, Health Technology Assessment (HTA) is an important tool for advancing UHC. The development and application of HTA in India, including capacity building and establishing institutional mechanisms. We emphasized using the HTA approach within two components of the Ayushman Bharat programme, and the section concludes with lessons learned and the next steps. The UHC has increased the importance of selecting and implementing effective technologies and interventions within national health systems, particularly in the context of limited resources. To maximize the use of limited resources and produce reliable scientific assessments, developing and enhancing national capacity must be based on established best practices, information exchange between different sectors, and collaborative approaches. A more potent mechanism and capacity for HTA in India would accelerate the country’s progress toward UHC.

BackgroundThe Egyptian healthcare system is currently in the early phase of health technology assessment (HTA) implementation. The aim of this study is to propose an implementation roadmap based on the national healthcare system status.MethodsA survey was conducted among Egyptian healthcare sector decision-makers to assess the current and future (preferred) HTA implementation status in Egypt based on a widely used international scorecard methodology. Subsequently, interviews were conducted with experts representing middle- and top-tier management in the Egyptian healthcare system to interpret the survey results and recommend specific actions.ResultsExperts recommended more capacity-building programs for HTA and health economics. Additionally, they proposed establishing HTA units in separate healthcare authorities and merging them into a single central HTA unit in the long term. Regarding the scope of implementation, experts recommended commencing with the assessment of innovative pharmaceuticals, and thereafter, expanding the scope to cover all health technologies in the long term. Additionally, they recommended using innovative tools such as “multi-criteria decision analysis (MCDA)” for tendering, and “managed entry agreements” for reimbursement decisions. Local burden of diseases and costing studies were also recommended to facilitate the implementation of HTA.ConclusionExperts agreed that several actions are required for successful HTA implementation in Egypt, including coordination between HTA bodies, application of an explicit MCDA framework, and strengthening of local evidence generation. To implement these actions, investment in technical capacity-building is indispensable. Most experts favored using multiple and soft cost-effectiveness thresholds. Efforts should be made to publish HTA submission guidelines and timelines of the processes.

BackgroundHealth Technology Assessment (HTA) is a multidisciplinary process that synthesizes, with a systematic, transparent, impartial and robust methodological approach, the main information on the medical, economic, ethical and social implications of the use and dissemination of a health technology. Its aim is to support decision-makers in identifying safe, effective, patient-centered and best-value health policies, in order to promote an equitable, efficient, and high-quality health system. Given the continued application of innovative technologies into clinical practice, healthcare professionals need to be able to adequately evaluate these technologies using evidence-based approaches such as HTA. Therefore, the implementation of training in HTA is crucial. The aim of this study was to investigate existing HTA training initiatives for healthcare professionals provided by international HTA agencies and organizations around the world.MethodsFrom March to November 2020, the websites of HTA agencies and organizations belonging to the European network for HTA (EUnetHTA) and to the International Network of Agencies for HTA (INAHTA), and the website of the HTA International (HTAi), were explored for identifying the HTA training initiatives directed to healthcare professionals. In addition, we screened the training initiatives proposed at European level by EUnetHTA as part of its Joint Actions and conducted in collaboration with its public-private partners. Specific keywords were searched in English and adapted to French, Portuguese, Spanish, Italian and German. Data extraction of the retrieved training initiatives was conducted from November 2020 to February 2021 and considered the following information: agency, country, website, coordinator, type of initiative, target, topic, main contents, and language.ResultsOut of 124 agencies/organizations/EUnetHTA public-private partners screened, only 21 provided training initiatives for healthcare professionals. A total of 55 training initiatives were analyzed, 85.5% of which were delivered at the European level and 14.5% at the international level. The countries with a greater number of courses were: Austria, Argentina, Spain, Portugal, and the United Kingdom. Twenty-one training initiatives focused on HTA application and methodology while 34 on specific HTA domains, particularly on the economic one. The technologies covered were mainly drugs.ConclusionsOur study revealed a limited number of HTA training programs targeting healthcare professionals. HTA supports the decision-making processes concerning the use and application of health technologies with scientific evidence. Indeed, training of healthcare professionals in this field should be a key driver in implementing evidence-based healthcare choices and through rigorous methodological approaches such as HTA, in order to ensure proper health governance and value-based application of technological innovations in clinical practice. Therefore, capacity building of healthcare professionals in this area should be enhanced by using appropriate and effective training initiatives and educational strategies.

IntroductionIt is well acknowledged that the price of orphan drugs is normally higher than that resulting from the value-based pricing. A correlation between the cost of therapy for orphan drugs and the epidemiology (prevalence and incidence) of the related rare disease can be hypothesized.MethodsThis analysis includes all approved orphan drugs by European Medicines Agency whose reimbursement was granted for the first therapeutic indication in the years 2014–2019 in Italy. Regression and correlation analyses were performed to analyze the possible correlations between the logarithm of the annual therapy cost and the epidemiology of the rare diseases, between orphan drugs consumption and epidemiology of related rare disease and between therapy cost and the consumption.ResultsThe regression analysis between the annual cost of therapy estimated on the published ex-factory price and the prevalence showed a slightly decreasing, not statistically significant, trend (coefficient: −0.10, p-value: 0.41). The results were similar when using the price resulting from the application of Managed Entry Agreements (coefficient: −0.11, p-value: 0.40). The regression analysis between sales volume and prevalence showed a positive slope without an acceptable level of significance (p-value: 0.04). The correlation analysis between the therapy cost and the sales volume highlighted again an absence of significant association, similarly if considering only ATC L orphan drugs, or the incidence.DiscussionThe definition of the price of an orphan drug seems not to depend on the rarity of the disease, and sales volumes do not correlate with the epidemiology of the rare disease and with the annual cost of therapy.

Introduction: The significant therapeutic potential of the advanced therapies (ATs) has predetermined the increased interests in their development mainly in the context of rare diseases most of which are genetically determined. However, there are still many challenges in front of the health insurance funds related to the cost-effectiveness and budget impact issues of these therapies. Our aim was to review and analyze the potential of low- and middle-income countries for health technology assessment (HTA) of advanced therapies focusing on Bulgaria, Romania and Poland as reference countries. A literature review of the existing good practices related to HTA of advanced therapies across the world and comparison with the national reality were performed. A list of challenges and issues from the point of view of the payer institution of all analyzed countries was performed. Pilot recommendations on how to overcome the barriers were created based on the existing practices and the potential of the national system.Discussion: 15 out of 80 articles identified in PubMed were found as applicable to the study scope as most of them were published in the period 2019–2021. Undoubtedly, the main challenges correspond to the high treatment costs, the uncertainty in clinical effectiveness, and poor HTA methodological approaches applicable for ATs worldwide. The issues identified for low and middle-income countries are similar having as well the lack of enough qualified health economists for the purposes of assessment and appraisal of HTA dossiers of the advanced therapies, lack of adequate existing separate financial programs for those therapies, and not preparedness of the health system and the society as a whole for such therapies.Conclusions: Despite the difficulties and challenges, the advanced therapies can be defined as a futuristic therapy for which great discoveries are yet to come. Therefore, each country should consider the implementation of reliable and nationally oriented programs for HTA and adequate financial coverage of these therapies.

The need to optimize drug development and facilitate faster access for patients has ignited discussions around the importance of improving interactions between health technology assessment (HTA) bodies and regulatory agencies. In this study, we conducted a systematic review to examine processes, progress, outcomes, and challenges of harmonization/interaction initiatives between HTA bodies and regulatory agencies. MEDLINE, EMBASE, and the International Pharmaceutical Abstracts database were searched up to 21 October 2019. Searches for gray literature (working papers, commissioned reports, policy documents, etc.) were performed via Google scholar and several institutional websites. An online cross-sectional survey was also conducted among HTA (n = 22) and regulatory agencies (n = 6) across Europe to supplement the systematic review. Overall, we found that while there are areas of divergence, there has been progress over time in narrowing the gap in evidentiary requirements for HTA bodies and regulatory agencies. Most regulatory agencies (4/6; 67%) and half (11/22, 50%) of the HTA bodies reported having a formal link for “collaborating” with the other. Several mechanisms such as early tripartite dialogues, parallel submissions (reviews), adaptive licensing pathways, and postauthorization data generation have been explored as avenues for improving collaboration. A number of pilot initiatives have shown positive effects of these models to reduce the time between regulatory and HTA decisions, which may translate into faster access for patients to life-saving therapies. Thus, future approaches aimed at improving harmonization/interaction between HTA bodies and regulatory agencies should build on these existing models/mechanisms while examining their long-term impacts. Several barriers including legal, organizational, and resource-related factors were also identified, and these need to be addressed to achieve greater alignment in the current regulatory and reimbursement landscape.

Introduction: Public health (PH) interventions are crucial for ensuring sustainable healthcare services. Nevertheless, they represent a neglected area in the field of health technology assessment (HTA) due to various methodological issues and their complex design that goes beyond clinical setting. The present study provides an environmental scan of HTA initiatives related to the assessment of PH technologies on a global level.Methods: We conducted a cross-sectional survey among 85 HTA-related European and international societies, health bodies, and networks from September 2018 to January 2019. The questionnaire contained four sections and 18 questions regarding activities related to the evaluation of PH technologies, information on existing PH technologies, and methodologies of assessment as well as barriers and facilitators to reaching a decision and implementing a PH technology.Results: Among 52 survey responses, the majority of the respondents came from European countries (35%), followed by North American (27%), and South American (19%) countries. The main type of organizations covered by our survey included HTA agencies, public administrations, and research institutes. Seventy-one % of the institutions reported engagement in any aspect of HTA in the area of PH (N = 37). Among those, 81% evaluated less than 5 PH technologies from 2013 to 2018. The most common barriers for reaching a decision on PH technologies were lack of data, conflicting stakeholder priorities, and methodological issues. A total of 76 PH interventions were reported, and most cited initiatives were related to chronic disease screening, prevention of infectious diseases, and maternal, prenatal, and neonatal screening.Conclusion: Our survey reported a rather limited involvement of HTA in the evaluation of PH technologies. In particular, an evaluation of behavioral and lifestyle interventions remains extremely rare. The implementation of collaborative HTA approaches in the setting of PH practice and policy needs to be prioritized and further strengthened. Moreover, ensuring reliable data structures and consolidation of HTA methods for the evaluation of PH technologies will be crucial for tackling the enormous burden of non-communicable diseases in societies.

Background: Multi-criteria decision analysis (MCDA) is a decision-making tool that can take into account multidimensional factors and enables comparison of (medical) technologies by combining individual criteria into one overall appraisal. The MCDA approach has slowly gained traction within Health Technology Assessment (HTA) and its elements are gradually being incorporated into HTA across Europe. Several groups of scientists have proposed MCDA approaches targeted toward orphan drugs and rare diseases by including criteria specific to rare diseases. The goal of this article is to provide an overview of the current state of knowledge and latest developments in the field of MCDA in HTA for orphan drugs, to review existing models, their design characteristics, as well as to identify opportunities for further model improvement.Methods: A systematic literature search was conducted in January 2018 using four databases: MEDLINE (Pubmed), EBSCO HOST, EMBASE, and Web of science to find publications related to use of MCDA in the rare disease field (keywords: MCDA/orphan drug/rare disease and synonyms). Identified MCDA models were analyzed, e.g., structure, criteria, scoring, and weighting methodology.Results: Two hundred and eleven publications were identified, of which 29 were included after removal of duplicates. 9 authors developed own MCDA models, 7 of which based on literature reviews intended to identify the most important and relevant decision criteria in the model. In 13 publications (8 models) weights were assigned to criteria based on stakeholder input. The most commonly chosen criteria for creation of the MCDA models were: comparative effectiveness/efficacy, the need for intervention, and disease severity. Some models have overlapping criteria, especially in the treatment cost and effectiveness areas.Conclusions: A range of MCDA models for HTA have been developed, each with a slightly different approach, focus, and complexity, including several that specifically target rare diseases and orphan drug appraisal. Models have slowly progressed over the years based on pilots, stakeholder input, sharing experiences and scientific publications. However, full consensus on model structure, criteria selection and weighting is still lacking. A simplification of the MCDA model approach may increase its acceptance. A multi-stakeholder discussion on fundamental design and implementation strategies for MCDA models would be beneficial to this end.

The main aim of health technology assessment (HTA) is to inform decision making by health care policy makers. It is a systematic process that evaluates the use of health technologies and generally involves a critical review of international evidence related to clinical effectiveness of the health technology vs. the best standard of care. It can also include an evaluation of cost effectiveness, and social and ethical impacts in the local health care system. The HTA process advises whether or not a health technology should be used, and if so, how it is best used and which patients are most likely to benefit from it. The importance of patient involvement in HTA is becoming widely recognized, for scientific and democratic reasons. The extent of patient involvement in HTA varies considerably across Europe. Commonly HTA is still focused on quantitative evidence to determine clinical and/or cost effectiveness, but the interest in understanding patients' experiences and preferences is increasing. Some HTA bodies provide support for participation in their processes, but again this varies widely across Europe. The involvement of patients in HTA is determined at the national and regional level, and is not subject to any European-wide legislation. The guidance text presented in this article was developed as part of the work of the European Patients' Academy on Therapeutic Innovation (EUPATI) and covers the interaction between HTA bodies and patients and their representatives when medicines are being assessed. Other EUPATI guidance documents relate to patient involvement in pharmaceutical industry-led research and development, ethics committees, and regulatory authorities. The guidance provides recommendations for activities to support patient involvement in HTA bodies and specific guidance for individual HTA processes. It seeks to improve patient involvement, using the outcomes of published research and consensus-building exercises. It also draws on good practice examples from individual HTA bodies. The guidance is not intended to be prescriptive and should be used according to specific circumstances, national legislation, or the unique needs of each interaction. This article represents the formal publication of the HTA guidance text with discussion about recent progress in, and continuing barriers to, patient involvement in HTA.

Introduction: In Europe and beyond, the rising costs of healthcare and limited healthcare resources have resulted in the implementation of health technology assessment (HTA) to inform health policy and reimbursement decision-making. European legislation has provided a harmonized route for the regulatory process with the European Medicines Agency, but reimbursement decision-making still remains the responsibility of each country. There is a recognized need to move toward a more objective and collaborative reimbursement environment for new medicines in Europe. Therefore, the aim of this study was to objectively assess and compare the national reimbursement recommendations of 9 European jurisdictions following European Medicines Agency (EMA) recommendation for centralized marketing authorization.Methods: Using publicly available data and newly developed classification tools, this study appraised 9 European reimbursement systems by assessing HTA processes and the relationship between the regulatory, HTA and decision-making organizations. Each national HTA agency was classified according to two novel taxonomies. The System taxonomy, focuses on the position of the HTA agency within the national reimbursement system according to the relationship between the regulator, the HTA-performing agency, and the reimbursement decision-making coverage body. The HTA Process taxonomy distinguishes between the individual HTA agency's approach to economic and therapeutic evaluation and the inclusion of an independent appraisal step. The taxonomic groups were subsequently compared with national HTA recommendations.Results: This study identified European national reimbursement recommendations for 102 new active substances (NASs) approved by the EMA from 2008 to 2012. These reimbursement recommendations were compared using a novel classification tool and identified alignment between the organizational structure of reimbursement systems (System taxonomy) and HTA recommendations. However, there was less alignment between the HTA processes and recommendations.Conclusions: In order to move forward to a more harmonized HTA environment within Europe, it is first necessary to understand the variation in HTA practices within Europe. This study has identified alignment between HTA recommendations and the System taxonomy and one of the major implications of this study is that such alignment could support a more collaborative HTA environment in Europe.

Introduction: In Europe and beyond, the rising costs of healthcare and limited healthcare resources have resulted in the implementation of health technology assessment (HTA) to informhealth policy and reimbursement decision-making. European legislation has provided a harmonized route for the regulatory process with the European Medicines Agency, but reimbursement decision-making still remains the responsibility of each country. There is a recognized need to move toward a more objective and collaborative reimbursement environment for new medicines in Europe. Therefore, the aim of this study was to objectively assess and compare the national reimbursement recommendations of 9 European jurisdictions following European Medicines Agency (EMA) recommendation for centralized marketing authorization. Methods: Using publicly available data and newly developed classification tools, this study appraised 9 European reimbursement systems by assessing HTA processes and the relationship between the regulatory, HTA and decision-making organizations. Each national HTA agency was classified according to two novel taxonomies. The System taxonomy, focuses on the position of the HTA agency within the national reimbursement system according to the relationship between the regulator, the HTA-performing agency and the reimbursement decision-making coverage body. The HTA Process taxonomy distinguishes between the individual HTA agency's approach to economic and therapeutic evaluation and the inclusion of an independent appraisal step. The taxonomic groups were subsequently compared with national HTA recommendations. Results: This study identified European national reimbursement recommendations for 102 new active substances (NASs) approved by the EMA from 2008 to 2012. These reimbursement recommendations were compared using a novel classification tool and identified alignment between the organizational structure of reimbursement systems (System taxonomy) and HTA recommendations. However, there was less alignment between the HTA processes and recommendations. Conclusions: In order to move forward to a more harmonized HTA environment within Europe, it is first necessary to understand the variation in HTA practices within Europe. This study has identified alignment between HTA recommendations and the System taxonomy and one of the major implications of this study is that such alignment could support a more collaborative HTA environment in Europe. [ABSTRACT FROM AUTHOR]

Recently, we established a pharmacodynamic assay to monitor immunosuppressive effectiveness of cyclosporine A (CsA) in patients on standard CsA regimen. The aim of the present study was to extend this correlation to reduced CsA regimen and to compare pharmacodynamic and kinetic parameters to allow prediction of rejections and infections. In 53 heart allograft recipients, nuclear factor of activated T cells (NFAT)-regulated gene expression was quantified at trough (C0) and 2-h post-CsA dose (C2). Gene expression at C2 was calculated relative to C0 (residual gene expression, RGE) or relative to a healthy reference group (absolute gene expression, AGE). RGE correlated with CsA C2-levels in bimodal fashion: above 575 ng/ml correlation was seen with flat regression gradient. Below 575 ng/ml, correlation was excellent with markedly steeper gradient. At C0 in the low-C2 group (<575 ng/ml), AGE remained unchanged, whereas in the high-C2 group (>575 ng/ml) AGE was markedly reduced. In both groups, AGE at C2 was strongly inhibited. In patients contracting infection during follow-up, RGE was lower than in those without infections independent of CsA levels. CsA-monitoring by quantitation of NFAT-regulated gene expression is feasible with standard and reduced CsA regimens. It correlates better with the incidence of infections than measurement of CsA concentrations and might help in avoiding over-immunosuppression. [ABSTRACT FROM AUTHOR]