Lessons learned from postmarketing withdrawals of expedited approvals for oncology drug indications.

In the past decade, there have been a record number of oncology therapy approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Besides the EMA's conditional marketing authorisation programme and the FDA's Accelerated Approval Program, we observe a tendency towards fast approval for exploratory studies with non-randomised, uncontrolled designs and surrogate endpoints. This issue raises concerns about the robustness and effectiveness of accepted treatments, leaving patients and health-care professionals in a state of uncertainty. A substantial number of accelerated approvals have recently been withdrawn in the USA, with some still authorised in Europe, emphasising discrepancies in regulatory standards that affect both patients and society as a whole. We highlight examples of drugs, authorised on the basis of surrogate endpoints, that were later withdrawn due to an absence of overall survival benefit. Our findings address the challenges and consequences of accelerated approval pathways in oncology. In conclusion, this Policy Review calls for regulatory bodies to better align their procedures and insist on robust evidence, preferably through unbiased randomised controlled trials. Drug approval processes should prioritise patient benefit, overall survival, and quality of life to minimise risks and uncertainties for patients.

Outcome-based reimbursement in Central-Eastern Europe and Middle-East.

Outcome-based reimbursement models can effectively reduce the financial risk to health care payers in cases when there is important uncertainty or heterogeneity regarding the clinical value of health technologies. Still, health care payers in lower income countries rely mainly on financial based agreements to manage uncertainties associated with new therapies. We performed a survey, an exploratory literature review and an iterative brainstorming in parallel about potential barriers and solutions to outcome-based agreements in Central and Eastern Europe (CEE) and in the Middle East (ME). A draft list of recommendations deriving from these steps was validated in a follow-up workshop with payer experts from these regions. 20 different barriers were identified in five groups, including transaction costs and administrative burden, measurement issues, information technology and data infrastructure, governance, and perverse policy outcomes. Though implementing outcome-based reimbursement models is challenging, especially in lower income countries, those challenges can be mitigated by conducting pilot agreements and preparing for predictable barriers. Our guidance paper provides an initial step in this process. The generalizability of our recommendations can be improved by monitoring experiences from pilot reimbursement models in CEE and ME countries and continuing the multistakeholder dialogue at national levels.

Kidney involvement in tuberous sclerosis complex: the impact on healthcare resource use and costs.

OBJECTIVE: Tuberous sclerosis complex (TSC) is associated with non-malignant kidney lesions-angiomyolipomata-that may be associated with chronic kidney disease (CKD). This study investigated the relationship between renal angiomyolipomata and CKD in TSC, including the impact on healthcare resource utilization (HCRU) and costs. METHODS: This was a retrospective, longitudinal cohort study based on medical record data spanning January 1990-April 2012 for 369 TSC patients treated at a specialty center in the Netherlands. Cohorts were established based on CKD stage and angiomyolipoma size. Rates of HCRU (physician visits, monitoring, and interventions) were compared across cohorts using rate ratios. Healthcare costs were compared across cohorts using cost differences. Regression models were used to identify predictive factors for HCRU and healthcare costs. RESULTS: Sixteen per cent of patients reached CKD stage 3 or higher during follow-up. Patients at more advanced stages of CKD more frequently had either large or multiple small angiomyolipomata and higher HCRU rates and healthcare costs. In the multivariate analyses, male gender, CKD stage >1, angiomyolipoma size ≥3.5 cm, embolization, and the presence of moderate or severe lymphangioleiomyomatosis (LAM) were associated with greater HCRU (p ≤ 0.002 for all comparisons). Definite (vs suspected) TSC diagnosis, CKD stage 5 (vs CKD stage 1), angiomyolipoma size ≥3.5 cm, and moderate or severe LAM were associated with higher costs (p = 0.050 for TSC diagnosis, p ≤ 0.002 for other comparisons). Costs in CKD stage 5 were driven primarily by dialysis. CONCLUSIONS: A substantial proportion of patients with TSC developed moderate-to-severe CKD, which was associated with renal angiomyolipomata and increased HCRU and costs.

Long-term Follow-up Assessing Renal Angiomyolipoma Treatment Patterns, Morbidity, and Mortality: An Observational Study in Tuberous Sclerosis Complex Patients in the Netherlands.

BACKGROUND: Long-term data from patients with tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (angiomyolipoma) are limited. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Adult patients with TSC treated at the University Medical Center Utrecht (the Netherlands) from January 1990 through April 2012. PREDICTORS: Patient age and angiomyolipoma stage, based on computed tomography lesion count, size, and impact on renal anatomy, with higher stage representing higher angiomyolipoma burden. Patients in stages 3 or higher were considered at high risk for hemorrhage and candidates for selective arterial embolization. OUTCOMES: Kidney-related outcomes included hypertension, anemia, decreased kidney function, dialysis, kidney transplantation, nephrectomy, kidney-related blood transfusions, and mortality. Observed mortality was compared to the Dutch National Bureau of Statistics using standardized mortality ratio. RESULTS: Median follow-up was 15.8 years, of which staging was available for 5.4 years. Of 351 patients with TSC, 244 (69.5%) had confirmed angiomyolipoma; 144 (59.0%) reached stage 3 or higher. Age and angiomyolipoma stage were positively correlated: median age in the none-detected stage was 36.8 years, increasing to 43.6 years for stage 6. Embolization was performed in 117 patients; 57 had 2 or more embolization procedures. Higher stage was associated with hypertension, anemia, decreased kidney function, and transfusion. Hypertension, anemia, and decreased kidney function were more common in patients who underwent selective arterial embolization. 7 patients required dialysis, 7 received a kidney transplant, and 16 underwent nephrectomy. 29 deaths were recorded, most commonly related to renal complications (n=9[31%]). Mortality was significantly higher in the study cohort versus the general population (standardized mortality ratio, 4.8; 95% CI, 3.4-6.9). LIMITATIONS: Duration of follow-up with staging was too short to observe stage progression in most patients. CONCLUSIONS: Despite the use of preventive selective arterial embolization, patients with TSC exhibit clinically significant kidney disease and excess mortality, largely because of kidney-related complications.

Intrauterine exposure to flavonoids modifies antioxidant status at adulthood and decreases oxidative stress-induced DNA damage.

Maternal intake of flavonoids, known for their antioxidant properties, may affect the offspring's susceptibility to developing chronic diseases at adult age, especially those related to oxidative stress, via developmental programming. Therefore, we supplemented female mice with the flavonoids genistein and quercetin during gestation, to study their effect on the antioxidant capacity of lung and liver of adult offspring. Maternal intake of quercetin increased the expression of Nrf2 and Sod2 in fetal liver at gestational day 14.5. At adult age, in utero exposure to both flavonoids resulted in the increased expression of several enzymatic antioxidant genes, which was more pronounced in the liver than in the adult lung. Moreover, prenatal genistein exposure induced the nonenzymatic antioxidant capacity in the adult lung, partly by increasing glutathione levels. Prenatal exposure to both flavonoids resulted in significantly lower levels of oxidative stress-induced DNA damage in liver only. Our observations lead to the hypothesis that a preemptive trigger of the antioxidant defense system in utero had a persistent effect on antioxidant capacity and as a result decreased oxidative stress-induced DNA damage in the liver.

Maternal quercetin intake during pregnancy results in an adapted iron homeostasis at adulthood.

The flavonoid quercetin is a powerful iron chelator, capable of oxidizing heme iron in hemoglobin from Fe(2+) to Fe(3+). Moreover, quercetin crosses the placenta and accumulates in the fetus. Since adaptations made by the fetus to cope with inappropriate nutrition may lead to permanent changes, a relative high intake of quercetin may have detrimental affects later in life. Therefore, we investigated the effects of maternal exposure to quercetin (302 mg/kg feed), starting from 3 days before conception until the end of gestation, on erythropoiesis and iron homeostasis at embryonic day 14.5 and in 12-week old mice. During fetal development, quercetin exposure had no effect on the erythroid lineage switch and concomitant globin switch. However, adult mice prenatally exposed to quercetin had significant increase iron storage in the liver, by upregulating iron-associated cytokine expression (hepcidin, IL-1ß, IL-6 and IL-10). These long term changes in gene expression could be mediated through epigenetic modifications, as prenatal quercetin exposure resulted in a modest hypermethylation of repetitive elements. Despite the increased iron levels, oxidative stress was significantly decreased in the liver of these animals as assessed by 8-oxo-dG levels. These data suggest that prenatal quercetin exposure results in increased iron storage, while decreasing oxidative stress induced DNA damage together with a shift towards increased expression of inflammation associated cytokines in the liver at adult age.

Prenatal exposure to flavonoids: implication for cancer risk.

Flavonoids are potent antioxidants, freely available as high-dose dietary supplements. However, they can induce DNA double-strand breaks (DSB) and rearrangements in the mixed-lineage leukemia (MLL) gene, which are frequently observed in childhood leukemia. We hypothesize that a deficient DSB repair, as a result of an Atm mutation, may reinforce the clastogenic effect of dietary flavonoids and increase the frequency of Mll rearrangements. Therefore, we examined the effects of in vitro and transplacental exposure to high, but biological amounts of flavonoids in mice with different genetic capacities for DSB repair (homozygous/heterozygous knock-in for human Atm mutation [Atm-ΔSRI] vs. wild type [wt]). In vitro exposure to genistein/quercetin induced higher numbers of Mll rearrangements in bone marrow cells of Atm-ΔSRI mutant mice compared with wt mice. Subsequently, heterozygous Atm-ΔSRI mice were placed on either a flavonoid-poor or a genistein-enriched (270 mg/kg) or quercetin-enriched (302 mg/kg) feed throughout pregnancy. Prenatal exposure to flavonoids associated with higher frequencies of Mll rearrangements and a slight increase in the incidence of malignancies in DNA repair-deficient mice. These data suggest that prenatal exposure to both genistein and quercetin supplements could increase the risk on Mll rearrangements especially in the presence of compromised DNA repair.