A Dutch cost-effectiveness analysis of fremanezumab versus best supportive care in patients with chronic migraine and inadequate response to prior preventive therapy.

BACKGROUND: Chronic migraine (CM) is the most severe and burdensome subtype of migraine. Fremanezumab is a monoclonal antibody that targets the calcitonin gene-related peptide pathway as a migraine preventive therapy. This study aimed to conduct a cost-effectiveness analysis of fremanezumab from a societal perspective in the Netherlands, using a Markov cohort simulation model. METHODS: The base-case cost-effectiveness analysis adhered to the Netherlands Authority guidelines. Fremanezumab was compared with best supportive care (BSC; acute migraine treatment only) in patients with CM and an inadequate response to topiramate or valproate and onabotulinumtoxinA (Dutch patient group [DPG]). A supportive analysis was conducted in the broader group of CM patients with prior inadequate response to 2-4 different classes of migraine preventive treatments. One-way sensitivity, probabilistic sensitivity, and scenario analyses were conducted. RESULTS: Over a lifetime horizon, fremanezumab is cost saving compared with BSC in the DPG (saving of €2514 per patient) and led to an increase of 1.45 quality-adjusted life-years (QALYs). In the broader supportive analysis, fremanezumab was cost effective compared with BSC, with an incremental cost-effectiveness ratio of €2547/QALY gained. Fremanezumab remained cost effective in all sensitivity and scenario analyses. CONCLUSION: In comparison to BSC, fremanezumab is cost saving in the DPG and cost effective in the broader population.

10% Body weight (gain) change as criterion for the maximum tolerated dose: A critical analysis.

The concept of the Maximum Tolerated Dose (MTD) was introduced in the seventies for carcinogenicity testing and was defined as the highest dose inducing clear toxicity, but not mortality by causes other than cancer. As estimation of the MTD in a carcinogenicity study, the highest dose that causes a 10% decrease in body weight compared to control animals over the course of a 90-day study, was formulated as a suitable criterion. This criterion was not seen as indicator of excessive toxicity but as a means to avoid false negative outcomes in a carcinogenicity study, as tumor formation may be reduced when body weight is significantly decreased. The body weight-based MTD criterion, however, turned up in carcinogenicity test guidelines and guidance (e.g., from OECD) as the highest dose that causes a 10% decrease in body weight gain relative to controls. Moreover, the 10% decrease in body weight gain criterion for MTD also ended up in test guidelines and guidances for toxicity endpoints other than carcinogenicity, so outside the context it was intended for. A 10% decrease in body weight gain relative to controls is however not a biologically relevant effect as it corresponds to less than 3% body weight reduction relative to controls in a 90-day study, which is within the normal variation in body weight. It therefore should certainly not be considered as a condition of excessive toxicity. Using the 10% lower weight gain criterion and incorrectly associating it with excessive toxicity has major implications for top dose selection in regulatory safety studies, resulting in tests performed at doses too low to elicit toxicity. This negatively impacts the reliability of studies and their regulatory usability; moreover, it results in a waste of experimental animals, which is ethically highly undesirable. Hence, our plea is to remove this MTD criterion for top dose selection in test guidelines and guidances for toxicity endpoints other than carcinogenicity and to reinstall the original 10% decrease in body weight criterion in test guidelines and guidances for carcinogenicity.

Regulating human safety: How dose selection in toxicity studies impacts human health hazard assessment and subsequent risk management options.

In the EU, one of the key determinants in the regulation and management of substances to ensure adequate protection of human health is the outcome of toxicity studies. These studies should therefore be performed in a way that the data generated are adequate to fulfil all regulatory requirements. However, in recent years, an increasing number of toxicity studies use dose levels that induce only slight, or even no toxicity, while the top dose lies well below the limit dose of 1000 mg/kg bw/d. The results of these studies have limited value for the hazard and subsequent risk assessment and risk management of substances. This paper shows why conducting toxicity studies with too low doses has severe consequences for among others classification and labelling, identification of endocrine disruptors, health impact assessment, and incident management. With this paper we aim to raise awareness on this issue and want to stress the importance of the use of sufficiently high dosing in toxicity studies. Given their central role in toxicity testing, it is therefore key to adapt where necessary the descriptions in OECD test guidelines and guidance documents on requirements for dose level setting, to make sure they are as explicit and unambiguous as possible.

Use of the kinetically-derived maximum dose concept in selection of top doses for toxicity studies hampers proper hazard assessment and risk management.

The KMD (kinetically-derived maximum dose) is an increasingly advocated concept that uses toxicokinetic data in the top dose selection for toxicity testing. Application of this concept may have serious regulatory implications though, especially in the European Union. The basic assumption is that the relationship between internal and external dose (IED) shows an inflection point where linearity transits into non-linearity due to saturation of underlying processes; top doses in toxicity tests should not be above the inflection point, provided human exposures are well below this point. A critical analysis of the KMD concept and its underlying assumptions shows, however, that the IED relationship is non-linear over the whole dose range, without any point of inflection. The KMD concept thus aims to estimate a non-existing point, rendering it invalid for use in toxicity testing. Moreover, the concept ignores the key question in toxicology: What kind of toxic effects occur at which doses? These and several other reservations against the KMD concept are discussed and illustrated with three existing applications of the KMD approach. Hence, we recommend to abolish the KMD concept for selecting top doses in toxicity testing. This requires the updating of regulations, guidance documents and OECD test guidelines.

Safety assessment of the substances 'wax, rice bran, oxidised' and 'wax, rice bran, oxidised, calcium salt' for use in food contact materials.

The EFSA Panel on Food Contact Materials (FCM) assessed the safety of the substances 'wax, rice bran, oxidised' and 'wax, rice bran, oxidised, calcium salt', used as additives up to 0.3% in polyethylene terephthalate (PET), polyamide (PA), thermoplastic polyurethane (TPU), polylactic acid (PLA) and poly(vinyl chloride) (PVC) in contact with all food types for long-term storage at room temperature and below, after hot-fill and/or heating. The substances consist of the chemical classes wax esters, carboxylic acids, alcohols and calcium salts of acids, along with an unidentified organic fraction up to ■■■■■ w/w. Migration into 10% ethanol and 4% acetic acid was below 0.012 mg/kg for each chemical class, and about 0.001 mg/kg for the unidentified fraction. In isooctane, migration was up to 0.297 mg/kg food for wax esters, below 0.01 mg/kg food for the other chemical classes and about 0.02 mg/kg food for the unidentified fraction. The contact with dry food and food simulated by 20% ethanol were considered covered by the migration tests with aqueous simulants. Based on genotoxicity assays and compositional analyses, the constituents of the chemical classes did not raise a concern for genotoxicity. The potential migration of individual constituents or groups of chemically-related compounds of the unidentified fraction would result in exposures below (for aqueous food) and above (for fatty food) the threshold of toxicological concern for genotoxic carcinogens. Therefore, the FCM Panel concluded that the substances are not of safety concern for the consumer, if used as additives up to 0.3% w/w in PET, PLA and rigid PVC materials and articles intended for contact with all food types except for fatty foods, for long-term storage at room temperature and below, including hot-fill and/or heating up to 100°C for up to 2 h.

Synthetic turf pitches with rubber granulate infill: are there health risks for people playing sports on such pitches?

The presence of carcinogenic substances in rubber granulate made from old car tyres raised concerns that the use of this granulate as infill on synthetic turf pitches may cause leukaemia and lymphoma in young football players and goalkeepers. Limitations in a number of prior studies on the topic casted doubts on their conclusion that it was safe to play sports on such pitches. Rubber granulate samples from 100 Dutch synthetic turf pitches were analysed for 45 (all samples) or 79 substances (a subset). A subset of samples was additionally analysed for migration of polycyclic aromatic hydrocarbons (PAHs), phthalates and metals into sweat and the gastrointestinal tract, and for evaporation of volatile substances into air. Exposure scenarios were developed to estimate the exposure of amateur football players via the oral, dermal and inhalation route to the most hazardous substances in rubber granulate. Risks to human health were assessed by comparing toxicological reference values for these substances with the exposure estimates. A number of carcinogenic, mutagenic and reprotoxic substances were present in rubber granulate used on Dutch pitches. No concern was, however, identified for phthalates, benzothiazoles, bisphenol A and the metals cadmium, cobalt and lead, as their exposures were below the levels associated with adverse effects on health. PAHs appeared to be the substances of highest concern, but even they present no appreciable health risk with exposures resulting in additional cancer risks at or below the negligible risk level of one in a million. Our findings for a representative number of Dutch pitches are consistent with those of prior and contemporary studies observing no elevated health risk from playing sports on synthetic turf pitches with recycled rubber granulate. Based on current evidence, there is no reason to advise people against playing sports on such pitches.

Cost-effectiveness in Clostridium difficile treatment decision-making.

AIM: To develop a framework for the clinical and health economic assessment for management of Clostridium difficile infection (CDI). METHODS: CDI has vast economic consequences emphasizing the need for innovative and cost effective solutions, which were aim of this study. A guidance model was developed for coverage decisions and guideline development in CDI. The model included pharmacotherapy with oral metronidazole or oral vancomycin, which is the mainstay for pharmacological treatment of CDI and is recommended by most treatment guidelines. RESULTS: A design for a patient-based cost-effectiveness model was developed, which can be used to estimate the cost-effectiveness of current and future treatment strategies in CDI. Patient-based outcomes were extrapolated to the population by including factors like, e.g., person-to-person transmission, isolation precautions and closing and cleaning wards of hospitals. CONCLUSION: The proposed framework for a population-based CDI model may be used for clinical and health economic assessments of CDI guidelines and coverage decisions for emerging treatments for CDI.

Out-patient drug policy by clinical assessment rather than financial constraints? The gate-keeping function of the out-patient drug reimbursement system in The Netherlands.

Since 1991, the Dutch Price Reference System (DPRS) has aimed at a growth reduction of out-patient drug costs without loss of medical quality. New drugs are excluded unless they pass legally anchored clinical criteria, i.e. substitutability with accepted drugs (DPRS-list 1a, implies a reimbursement maximum), 'unique and valuable' (DPRS-list 1b, liberal price setting), or lack of value (rejected). We analysed the performance (transparency, judgement stability) of the gate-keeping function during July 1999-July 2002. For drugs applied for DPRS-list 1b status, we relate the satisfaction of existing and implicit criteria to being accepted or rejected. Of 85 DPRS-list 1b applicants, 20 were shifted to DPRS-list 1a, 52 were accepted, and 13 were rejected with different roles of therapeutic value, budget impact, and burden of disease, the latter emerging as a decisive yet non-legal criterion. The gate-keeping function of the DPRS offers a non-opportunistic balance between clinical and economic demands, provided the burden of disease criterion is implemented, and provides influential tools for financial constraints.

The European Union risk assessment on zinc and zinc compounds: the process and the facts.

A risk assessment on zinc and zinc compouns was carried out withn the framework of Council Regulation 793/93/EEC on Existing Chemicals. This risk assessment basically followed the European Union (EU) technical guidance documents (TGDs). These TGDs are built on the current knowledge on quantitative risk assessments, mainly for organic chemicals. This article describes the tailor-made approach for the zinc risk assessment. This work lasted almost a decade and involved the contributions of all EU member states and industry, who discussed the risk assessment during technical meetings. The risk assessment is initially based on scientific findings but is interrelated with pragmatic considerations. It follows a comprehensive approach, covering both environmental and human health. In the environmental part, new methodologies were developed to deal with the natural background of zinc, essentiality, speciation, and the use of species sensitivity distributions. The major results and the process of drawing conclusions of the risk assessment are outlined: potential environmental risks of zinc and zinc compounds may occur at local and regional scales in surfacewater, sediment, and soil. No potential health risks were identified for consumers and man indirectly exposed via the environment. For workers, potential health risks were identified only for zinc oxide and zinc chloride.