Shaping a suitable EU HTA dossier template: why the German template is not fit for purpose.

From 2025, Health Technology Developers (HTDs) have to submit EU HTA dossiers. The joint clinical assessment (JCA) aims to streamline HTA processes and access to medicinal products across Europe. Currently, German HTA bodies IQWiG and G-BA actively shape the JCA methodology. Here we examine if German HTA dossier requirements are suitable for the JCA. We compare the number of safety endpoint and subgroup analyses in German dossiers with analyses considered in IQWIG's benefit assessment and evaluate if these analyses were considered by the G-BA. We further investigated how the number of analyses was affected by the latest change in the German dossier template. With the current template, HTDs report in median 2.6 times more analyses on adverse events (AE) and 1.1 times more subgroup categories than in the previous template. IQWiG does not consider 33% of AE analyses and 73% of the subgroup categories presented by the HTD under the current template. G-BA considered the same AE as IQWiG in 76% of cases. Subgroups were uncommented by G-BA in most cases, independent of the template (previous: 93%, current 85%) and unconsidered in the conclusion on additional benefit (previous: 77%, current 69%). Thus, changes in the dossier template drastically increased HTD workload, but additional analyses seem unconsidered by the HTA bodies. With a broader scope in JCA, this effect could be amplified. To mitigate duplicative efforts and ensure prompt availability of medicinal products as envisioned by the HTAR, we suggest well-chosen and precise dossier requirements, early consultations, and early HTD engagement.

Towards compatibility of EUnetHTA JCA methodology and German HTA: a systematic comparison and recommendations from an industry perspective.

OBJECTIVE: The transferability of the EU joint clinical assessment (JCA) reports for pharmaceuticals for the German benefit assessment was evaluated by systematically comparing EU JCA and German clinical assessments (CA) based on established assessment elements for HTA and assessing the potential impact of differences on Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) ability to derive the therapeutic added value. METHODS: Identification of all pharmaceuticals undergoing both, EU JCA and German CA between January 2016-June 2020. Qualitative review and data extraction from the assessments, assessment of methodological differences using a hierarchical model. Recommendations for harmonisation were developed and consented with pharmaceutical industry stakeholders. RESULTS: Differences with potentially major impact: (1) View on differing treatment algorithms and definition of corresponding subpopulations/respective comparators. (2) Clinical relevance of surrogate/intermediate endpoints. Inclusion of different/surrogate morbidity endpoints resulting in different relative effectiveness conclusions. (3) Tolerance of study interventions not used according to marketing authorisation. (4) Different operationalisation and/or weighting of individual safety endpoints leading to differing relative safety conclusions. Differences with potentially minor impact: (1) Disagreement in risk of bias assessment for overall survival and its robustness against study limitations. (2) Use of patient-reported outcome symptom scales as measurements for health-related quality of life instruments. CONCLUSION: While many synergies between EU JCA and German CA exist, we identified several aspects in HTA methodology that would benefit of harmonisation and ensure the transferability of future EU JCA to the German HTA process without duplicated evaluation requirements. For those, a set of recommendations was developed.

[Subgroups in the early benefit assessment of pharmaceuticals: a methodical review]. / Subgruppen in der frühen Nutzenbewertung von Arzneimitteln: eine methodische Bestandsaufnahme.

Benefit assessments according to Sect. 35a of the Social Code Book V are frequently divided into subsets of populations. This division of therapeutic indications is evident in almost every other of the completed appraisals by the Federal Joint Committee (G-BA). The subsets can be deduced from the wording of the approved therapeutic indication (subpopulations) or from potential effect modification (subgroups). Methodological challenges are illustrated on the basis of current scientific knowledge of how to tackle subgroups. Practical assessment examples are used to explain the methods implemented by IQWiG and the G-BA and reveal major problem areas concerning subgroup analyses, subpopulations as well as mismatches between the requirements of early benefit assessment and approval. Overall, it appears there is a need for establishing a more comprehensive discussion regarding the validity of subgroup analyses and their associated limitations.

[Learning curve in laser treatment of benign prostatic syndrome: a systematic review]. / Lernkurve bei Laserverfahren in der Behandlung des benignen Prostatasyndroms: Ein systematischer Review.

The aim of the present systematic review was to evaluate the evidence of a potential learning curve for laser treatment of benign prostatic hyperplasia. A systematic literature search was conducted in November 2011 using The Cochrane Library, EMBASE and MEDLINE. Overall, 18 sources (mostly case series) were included for further assessment. The majority of publications assume that a general learning curve exists. It is estimated that a range of 20 to 50 cases is needed to achieve a stable outcome level. For the most part, these findings are based on the HoLEP (Holmium laser enucleation of prostate) technique and intraoperative measures, such as enucleation efficiency. Valid conclusions regarding patient-related end-points are difficult to make, although some studies report a decreasing trend for complication rates with increasing experience of the surgeon. No statistically significant differences were found for postoperative outcomes such as IPSS (International Prostate Symptom Score), Qmax (peak flow rate) or Quality of Life. Overall, the present results are highly limited by the low evidence level and methodological problems of the publications available. Several publications suggest that adequate training during the implementation phase is relevant.

[GRADE guidelines: 8. Rating the quality of evidence - indirectness]. / GRADE Leitlinien: 8. Einschätzung der Qualität der Evidenz - Indirektheit.

Direct evidence comes from research that directly compares the interventions in which we are interested when applied to the populations in which we are interested and measures outcomes important to patients. Evidence can be indirect in one of four ways. First, patients may differ from those of interest (the term applicability is often used for this form of indirectness). Second, the intervention tested may differ from the intervention of interest. Decisions regarding indirectness of patients and interventions depend on an understanding of whether biological or social factors are sufficiently different that one might expect substantial differences in the magnitude of effect. Third, outcomes may differ from those of primary interest - for instance, surrogate outcomes that are not themselves important, but measured in the presumption that changes in the surrogate reflect changes in an outcome important to patients. A fourth type of indirectness, which is conceptually different from the first three, occurs when clinicians must choose between interventions that have not been tested in head to head comparisons. Making comparisons between treatments under these circumstances requires specific statistical methods and will be rated down in quality by one or two levels depending on the extent of differences between the patient populations, co-interventions, measurements of the outcome, and the methods of the trials of the candidate interventions against some other comparator.

Determinants of willingness to pay for a new therapy in a sample of menopausal-aged women.

Menopause is a natural physiological event that usually begins in women between the ages of 48 and 55 years. In many cases, this event is associated with unpleasant somatic-vegetative, urogenital or psychological symptoms. To test the health and social demographic factors (especially household income level) that influence willingness to pay (WTP) for a new hormone-free treatment in women of menopausal age. 1365 women between the ages of 45 and 73 years were surveyed about their health and WTP for the new treatment. WTP was evaluated with a closed-ended binary questionnaire (four groups with different levels of co-payment between euro15 and euro60), using the contingent valuation method. The average WTP was calculated according to the area under the demand function. Factors contributing to payment readiness were examined by means of binary logistic regression. WTP was significantly affected by women's opinion of the new medication, the level of co-payment required, net household income, whether currently in treatment for menopausal symptoms, and Menopause Rating Scale (MRS) values. Compared with other factors, the level of co-payment was predicted to have a negative impact on WTP. Income level is an important factor in WTP and correlates highly with several other health-related variables (WHO-5 index, MRS value, receipt of other menopause medicines and existing co-morbidity). The average co-payment that our group of women was willing to pay was between euro17 and euro35 per month, or euro24 to euro42 for women who were currently receiving treatment for symptoms of menopause. While interpreting the results, it should be considered that the hypothetical therapy was assumed to be a new non-reimbursable alternative to conventional therapy offered under the existing statutory framework for health insurance in Germany. Despite some methodological limitations, these results are useful for examining the factors affecting WTP and incremental utilities for future medicine dealing with menopause.

Cataract surgery and the development or progression of age-related macular degeneration: a systematic review.

Age-related macular degeneration and cataract are the most frequent eye disorders of elderly people worldwide. The aim of this systematic review was to evaluate the effect of cataract surgery on the development and progression of age-related macular degeneration. Data were collected by means of a systematic literature search in 28 databases and an additional update in Pubmed. Search results were evaluated using pre-defined inclusion and exclusion criteria. All relevant publications were rated in terms of scientific quality and analyzed regarding their results. The literature search generated a total of 2,827 hits. Seven publications on five observational studies and two non-randomized clinical trials were eligible for analysis. The observational studies provided some evidence for an increased incidence of late age-related macular degeneration, respectively, for a promoting influence of cataract surgery on the progression of early types of age-related macular degeneration. The clinical trials did yield inconsistent results. In conclusion, only a small number of published studies investigated the development or progression of age-related macular degeneration following cataract surgery. The scientific level of evidence of these articles was not high and results were inconsistent, nevertheless a promoting influence of cataract surgery on the progression of early age-related macular degeneration can be assumed.

Effectiveness and cost-effectiveness of behavioural strategies in the prevention of cigarette smoking.

BACKGROUND: The hazardous health effects of smoking and second hand smoke have been confirmed in numerous studies. For Germany, the mortality attributable to smoking is estimated at 110,000 to 140,000 deaths per year, associated with annual smoking-related costs of 17 to 21 billion euro. Because the majority of smokers initiate this habit early in life, behavioural preventive strategies usually tried to prevent the uptake of smoking among children and youths. OBJECTIVES: The goal of this HTA is to summarise the current literature on behavioural strategies for smoking prevention and to evaluate their medical effectiveness/efficacy and cost-effectiveness as well as the ethical, social and legal implications of smoking prevention programs. In addition, this report aims to compare the effectiveness and efficacy of different intervention components and to evaluate the reliability of results in the German context. METHODS: Relevant publications were identified by means of a structured search of databases accessed through the German Institute of Medical Documentation and Information (DIMDI). In addition a manual search of identified reference lists was conducted. The present report includes German and English literature published between August 2001 and August 2006 targeting youths up to 18 years old. The methodological quality of included studies was assessed according to pre-defined quality criteria, based on the criteria of evidence-based medicine. RESULTS: Among 3,580 publications 37 medical studies met the inclusion criteria. Overall study quality was satisfactory but only half the studies reported smoking uptake as an outcome, while the remaining studies reported alternative outcome parameters. The follow-up duration varied between twelve and 120 months. Although overall effectiveness of prevention programs showed considerable heterogeneity, there was evidence for the long-term effectiveness of behavioural smoking prevention programs. However, the reduction in smoking rates was only moderate. Community and multisectorial interventions reported more conclusive evidence for reductions in smoking rates, while the evidence for school-based programs alone was inconclusive. Only one study from Germany fulfilled the methodological criteria and was included in this report. Three included economic studies focused on school-based interventions. Study results suggested, that the cost-effectiveness of school-based behavioural interventions is positive. DISCUSSION: Behavioural preventive strategies were effective to delay or decrease uptake of smoking behaviour among children and youth. The effect size, however, was only moderate. Similar to previous research, there was no conclusive evidence for the long-term effectiveness of school-based interventions, whereas community and multisectorial interventions provided more conclusive evidence. However, sustainability of intervention effects has to be regarded with caution. In addition, there is evidence that findings from international studies can be adapted to the German situation and that intervention effectiveness is comparable. The available evidence regarding the cost-effectiveness of school-based interventions is not sufficient to draw reliable conclusions. CONCLUSION: Behavioural preventive strategies can be effective in the prevention of smoking among children and youths. It seems advisable, though, to incorporate community strategies in addition to school-based strategies in order to improve their effectiveness. Future research should, amongst others, attempt to investigate the effectiveness of specific intervention components and the cost-effectiveness in methodologically high-quality studies.

What effects has the cataract surgery on the development and progression of Age-Related Macular Degeneration (AMD)?

BACKGROUND: The cataract (Cataracta senilis) is the most frequent eye disease of elderly people worldwide. In Germany, the cataract operation - with currently 450,000 interventions each year the most frequent operation in ophthalmology - can be seen as routine surgery. The age related macular degeneration (AMD) is a further one of the most common, age-related eye diseases and the most frequent cause of blindness of elderly people in industrial nations. Due to demographic changes an increasing number of patients will suffer from cataract and AMD at the same time. This coincidence leads to a greater interest in the question of a mutual influence of both diseases, respectively their therapies, on each other. OBJECTIVES: The aim of this report was the evaluation of the medical and health economic effects of cataract operations on the development and progression of an age related macular degeneration (AMD). It was differentiated between first manifestations of AMD, progression of early stages of AMD and influence on further impairment in late stages of AMD. METHODS: The relevant publications for this report were identified by DIMDI via structured database enquiry as well as common, self-made enquiry and were evaluated, based on the criteria of evidence based medicine. The present report included German and English literature published since 1983. RESULTS: The database enquiry generated a record of 2769 issue-related publications. Eight medical publications were eligible for analysis in the course of the present HTA report. No relevant studies on health economical, ethical, social or legal issues could be included. Three epidemiological cohort studies provided some evidence for a promoting influence of cataract extractions on the progression of early types of AMD. Two of the epidemiological studies assessed the risk of first manifestation of AMD after cataract extraction. Both came up with up with increased incidences that did not reach statistical significance despite a large number of participants. Only one out of two clinical studies looked at further impairment in late stages of AMD and could not find an interrelation with cataract extraction. Thus the available evidence was not sufficient to come to a conclusion on the contribution of cataract extractions to the first manifestation of AMD and to the further impairment in late stages. DISCUSSION: The presentation of the evaluated literature made clear that only a small number of publications dealt with the development of age related macula degeneration in consequence of a cataract extraction. The overall scientific level of evidence of these articles was not very high. Therefore it was not possible to obtain a well-defined conclusion on the effect of a cataract extraction on the development or progression of an age related macula degeneration. CONCLUSION: Additional well conducted clinical trials, that offer a sufficient number of patients, length of study period and adequate control for confounding variables like age and severity of cataract, are urgently needed. Health economic, ethical, social and legal aspect of the problem could and should be investigated after clarification of the mentioned medical issues.