Dynamic HTA for digital health solutions: opportunities and challenges for patient-centered evaluation.

OBJECTIVES: Germany's 2019 Digital Healthcare Act (Digitale-Versorgung-Gesetz, or DVG) created a number of opportunities for the digital transformation of the healthcare delivery system. Key among these was the creation of a reimbursement pathway for patient-centered digital health applications (digitale Gesundheitsanwendungen, or DiGA). Worldwide, this is the first structured pathway for "prescribable" health applications at scale. As of October 10, 2023, 49 DiGA were listed in the official directory maintained by Germany's Federal Institute for Drugs and Medical Devices (BfArM); these are prescribable by physicians and psychotherapists and reimbursed by the German statutory health insurance system for all its 73 million beneficiaries. Looking ahead, a major challenge facing DiGA manufacturers will be the generation of the evidence required for ongoing price negotiations and reimbursement. Current health technology assessment (HTA) methods will need to be adapted for DiGA. METHODS: We describe the core issues that distinguish HTA in this setting: (i) explicit allowance for more flexible research designs, (ii) the nature of initial evidence generation, which can be delivered (in its final form) up to one year after becoming reimbursable, and (iii) the dynamic nature of both product development and product evaluation. We present the digital health applications in the German DiGA scheme as a case study and highlight the role of RWE in the successful evaluation of DiGA on an ongoing basis. RESULTS: When a DiGA is likely to be updated and assessed regularly, full-scale RCTs are infeasible; we therefore make the case for using real-world data and real-world evidence (RWE) for dynamic HTAs. CONCLUSIONS: Continous evaluation using RWD is a regulatory innovation that can help improve the quality of DiGAs on the market.

Advancing digital health applications: priorities for innovation in real-world evidence generation.

In 2019, Germany passed the Digital Healthcare Act, which, among other things, created a "Fast-Track" regulatory and reimbursement pathway for digital health applications in the German market. The pathway explicitly provides for flexibility in how researchers can present evidence for new digital products, including the use of real-world data and real-world evidence. Against this backdrop, the Digital Medicine Society and the Health Innovation Hub of the German Federal Ministry of Health convened a set of roundtable discussions to bring together international experts in evidence generation for digital medicine products. This Viewpoint highlights findings from these discussions with the aims of (1) accelerating and stimulating innovative approaches to digital medical product evaluation, and (2) promoting international harmonisation of best evidentiary practices. Advancing these topics and fostering international agreement on evaluation approaches will be vital to the safe, effective, and evidence-based deployment and acceptance of digital health applications globally.

The effect of self-inflicted burns on ABSI score prediction power: A four-year prospective multicenter study of the German Burn Registry.

BACKGROUND: Suicide attempted by self-inflicted burns are associated with lower survival rates compared to accident related burns. OBJECTIVE: We investigate the relation between self-inflicted burns (SIB) and survival rates and how this relation is moderated by variables used to predict survival rates in the ABSI score, a widely used measure. Additionally, we compare the predicted survival rates by the ABSI score to the actual rates in our sample for SIB and accident patients. METHODS: In this prospective multicenter study data from the German Burn Registry are statistically analyzed using two sided t-test and multivariate linear regression models. RESULTS: 5330 patients (214 with SIB) met our inclusion criteria. We find a 6.8 percentage points lower survival rate for patients with SIB when we control for patient condition with the five ABSI components as covariates. These higher mortality rates can be explained by the higher rate of therapy restrictions for patients with self-inflicted burns. Additionally, different ABSI modifications can improve the predictive power of the score. CONCLUSION: Patients with SIB have lower survival rates compared to accident patients. Recently proposed modifications of the ABSI score can improve the accuracy of survival rate prediction for SIB.

Physician Behavior under Prospective Payment Schemes-Evidence from Artefactual Field and Lab Experiments.

Recent experimental studies analyze the behavior of physicians towards patients and find that physicians care for their own profit as well as patient benefit. In this paper, we extend the experimental analysis of the physician decision problem by adding a third party which represents the health insurance that finances medical service provision under a prospective payment scheme. Our results show that physicians take into account the payoffs of the third party, which can lead to underprovision of medical care. We conduct a laboratory experiment in neutral as well as in medical framing using students and medical doctors as subjects. Subjects in the medically framed experiments behave weakly and are more patient orientated in contrast to neutral framing. A sample of medical doctors exhibits comparable behavior to students with medical framing.

Increased instruction time and stress-related health problems among school children.

While several studies suggest that stress-related mental health problems among school children are related to specific elements of schooling, empirical evidence on this causal relationship is scarce. We examine a German schooling reform that increased weekly instruction time and study its effects on stress-related outpatient diagnoses from the universe of health claims data of the German Social Health Insurance. Exploiting the differential timing in the reform implementation across states, we show that the reform slightly increased stress-related health problems among school children. While increasing instruction time might increase student performance, it might have adverse effects in terms of additional stress.

Is it good to be too light? Birth weight thresholds in hospital reimbursement systems.

Birth weight manipulation has been documented in per-case hospital reimbursement systems, in which hospitals receive more money for otherwise equal newborns with birth weight just below compared to just above specific birth weight thresholds. As hospitals receive more money for cases with weight below the thresholds, having a (reported) weight below a threshold could benefit the newborn. Also, these reimbursement thresholds overlap with diagnostic thresholds that have been shown to affect the quantity and quality of care that newborns receive. Based on the universe of hospital births in Germany from the years 2005-2011, we investigate whether weight below reimbursement relevant thresholds triggers different quantity and quality of care. We find that this is not the case, suggesting that hospitals' financial incentives with respect to birth weight do not directly impact the care that newborns receive.

Poly Implant Prothèse and Rofil Substandard Breast Implant Explantations from a Large German Single Centre from 2011 to 2014: A Comparative Study.

BACKGROUND: Following a Europe-wide scandal, substandard breast implants containing silicone for industry purposes produced by Poly Implant Prothèse (PIP&Rofil) were explanted due to its potential health risks. OBJECTIVE: We investigated whether these implants actually imposed a threat to patients' health. METHODS: In this retrospective single-centre case-control study, we compared patients with breast augmentation receiving implant explantation (01/2011-01/2015). Data were collected retrospectively from the patients' records. Patients were split into two groups: PIP&Rofil and implants of other manufacturers. RESULTS: A total of 307 patients with 495 breast implants met the inclusion criteria, 64 patients with 115 PIP&Rofil implants and 243 patients with 380 implants of other manufacturers. Comparison of descriptive statistics between the two groups revealed that for a variety of indicators (e.g. patient age, breast cancer, aesthetic vs. reconstructive indication, implant volume, submuscular vs. subglandular implant position) PIP implants differ from non-PIP implant patients. Raw mean comparison showed higher rupture rates for non-PIP implants, 28.42 % (PIP 23.48 %). However, when controlling for implant indwelling time, PIP implants had shown higher rupture rates. Both groups had similar rates of capsular contracture (PIP: 71.30 %, Others: 72.63 %) with different distribution of Baker Scores (Baker 2/3/4: PIP 5/8/13 and non-PIP 3/24/135). CONCLUSION: Concerning patient symptoms, we did not find any objective reason to justify implant explantation of PIP&Rofil implants as a solely precautionary measure. As PIP&Rofil implants showed shorter retention periods until rupture and ruptured implants can cause symptoms or health problems, PIP&Rofil implants should be regularly monitored and explanted if there is evidence of rupture. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

DDT and urogenital malformations in newborn boys in a malarial area.

OBJECTIVE: To determine the risk of external urogenital birth defects (UGBDs) in newborn boys from a malarial area currently sprayed with technical 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (DDT), as increased fetal oestrogenic or anti-androgenic exposure might be involved in the pathogenesis of increased prevalence of human male reproductive tract anomalies, and DDT and metabolites interact with both these receptors. SUBJECTS AND METHODS: We examined 3310 newborn baby boys and recorded external UGBDs. RESULTS: Of the newborn boys 10.8% (357) had UGBDs; a multivariate logistic model showed that mothers who lived in villages sprayed with DDT between 1995 and 2003 had a significantly greater chance (33%) of having a baby with a UGBD than mothers whose homes were not sprayed (odds ratio 1.33, 95% confidence interval 1.04-1.72). Being a homemaker instead of being employed further significantly increased the risk of having a baby with a UGBD by 41% (odds ratio 1.41, 1.13-1.77). CONCLUSIONS: Maternal exposure to DDT by living in a DDT-sprayed village was associated to having male offspring with one or more UGBDs. Monitoring the impact of indoor residual spraying on human and environmental health is imperative if DDT is being used, especially as climate change raises concerns about the global spread of malaria. Integrating adequate indoor residual spraying measures by malarial vector control programmes, and increased public awareness to limit personal exposure, are crucial components that need to be addressed.

Triptorelin 6-month formulation in the management of patients with locally advanced and metastatic prostate cancer: an open-label, non-comparative, multicentre, phase III study.

BACKGROUND AND OBJECTIVES: Triptorelin 6-month formulation was developed to offer greater convenience to both patients and physicians by reducing the injection frequency. The efficacy, pharmacokinetics and safety of a new 6-month formulation of triptorelin were investigated over 12 months (48 weeks). The primary objective was to evaluate the formulation in achieving castrate serum testosterone levels (< or = 1.735 nmol/L or < or = 50 ng/dL) on day 29 and in maintaining castration at months 2-12. Absence of luteinizing hormone (LH) stimulation and change in prostate-specific antigen (PSA) level were also assessed. METHODS: An open-label, non-comparative, phase III study in 120 patients with advanced prostate cancer was conducted from July 2006 to August 2007 in private and public institutions in South Africa. Each patient received two consecutive intramuscular injections of triptorelin embonate (pamoate) 22.5 mg at an interval of 24 weeks. In all patients, testosterone (primary outcome measurement) was measured at baseline and then every 4 weeks; LH was measured before and 2 hours after the two injections. PSA was measured on day 1 and at weeks 12, 24, 36 and 48. Adverse events were recorded at each visit. RESULTS: In the intent-to-treat population, 97.5% (95% CI 92.9, 99.5) of patients achieved castrate serum testosterone levels by day 29, and 93.0% (95% CI 86.8, 97.0) maintained castration at months 2-12. After the second injection, 98.3% of patients showed absence of LH stimulation. The most frequent drug-related adverse events were hot flushes (71.7% of patients). No patient withdrew from the study as a result of an adverse event. CONCLUSIONS: The triptorelin 6-month formulation was well tolerated and was able to achieve and maintain castration for the treatment of locally advanced and metastatic prostate cancer. By reducing the frequency of required injections, this new formulation offers a more convenient treatment regimen. (Clinical Trial Registration,NCT00751790 at www.clinicaltrials.gov).

Ultrastructural changes of platelet aggregates and fibrin networks in a patient with renal clear cell adenocarcinoma: a scanning electron microscopy study.

A 47-year-old male patient presented with weight loss, hematuria, and a left renal mass, which proved to be a clear cell renal carcinoma with multiple liver, pulmonary and bone metastases. The platelet count was raised initially (414 x 10(9)/L) but declined 10 weeks after a debulking procedure followed by chemotherapy. Fibrin clots were prepared for scanning electron microscopy (SEM) by adding human thrombin to platelet rich plasma (derived by differential centrifugation of fresh blood samples taken from the patient as well as controls). The clots were washed, fixed in 2.5% glutaraldehyde and Dulbecos phosphate buffered saline and prepared for SEM with a Zeiss Ultra 55 FEG SEM. The SEM photographs revealed an altered morphology of the platelet aggregates with multiple breakages in the platelet membrane, showing a pock-marked, crenated, prune-like appearance as opposed to the smooth rounded globular membrane of the controls. The ultrastructural morphology of the fibrin bound platelet aggregates in this patient with renal carcinoma therefore showed a disrupted cytoskeletal architecture which appears to be similar to the apoptotic changes of programmed cell death as described by Bornman et al. (2007) and Pretorius et al. (2008). These features may well be a distinct ultrastructural hematological manifestation of a previously unidentified paraneoplastic syndrome.