A narrative review of estimands in drug development and regulatory evaluation: old wine in new barrels?

BACKGROUND: An estimand defines the target of estimation for a clinical trial through specification of the treatment, target population, variable, population-level summary and of the strategies for intercurrent events. A carefully defined estimand aligns the clinical trial design and analysis with the scientific question of interest and adequately accounts for so-called intercurrent events. The ICH E9(R1) addendum suggests five estimand strategies. We evaluated to what extent current practice in drug development and regulatory assessment fits in the estimand framework. METHODS: We systematically evaluated what estimands, especially what strategies for intercurrent events are advised in European Medicines Agency disease guidelines, used in sponsors' trials and additionally requested by the European Medicines Agency in assessment dossiers. We selected four therapeutic areas: nervous system, oncology, cardiovascular diseases and respiratory diseases. For each, we evaluated all disease guidelines with approved drugs, the dossiers of the most recently approved drugs matching the guidelines and corresponding regulatory questions. RESULTS: Strategies for intercurrent events were present in 18 (53%) of 34 guidelines, in all 34 sponsor documentations and in 15 (44%) of 34 sets of regulatory questions. Treatment policy was advised in 13 (38%) guidelines and was applied in 9 corresponding sponsor documentations. Of these 9, it was the sole strategy in 4 cases and accompanied by another strategy in 5 cases. Hypothetical strategy was not advised in guidelines. However, it was the leading strategy applied in 25 (74%) sponsor documentations. Composite strategy was advised in 3 (9%) guidelines and applied accompanied by another strategy in 2 corresponding sponsor documentations. While on treatment strategy was not advised in guidelines, but was applied in 2 sponsor documentations. Principal stratum strategy was advised in 2 guidelines but not applied in corresponding sponsor documentations. Of the regulatory questions, treatment policy was present in 2 cases (6%), hypothetical in 6 cases (18%), composite in 6 cases (18%) and while on treatment in 1 case (3%). CONCLUSIONS: Estimand attributes are present in guidelines, sponsor documentations and regulatory questions, but not described as estimands. Treatment policy was most often advised in guidelines, but hypothetical was the leading strategy applied in sponsor documentations. Thus, results indicate not a full concordance between the regulatory target of estimation and what is actually estimated. The lack of concordance was mostly due to limitations in collection of intercurrent events data to enable a treatment policy strategy. There is, therefore, a need to better define estimands at the design stage and throughout the applications dossiers and assessment reports.

FAIR data sharing: The roles of common data elements and harmonization.

The value of robust and responsible data sharing in clinical research and healthcare is recognized by patients, patient advocacy groups, researchers, journal editors, and the healthcare industry globally. Privacy and security concerns acknowledged, the act of exchanging data (interoperability) along with its meaning (semantic interoperability) across studies and between partners has been difficult, if not elusive. For shared data to retain its value, a recommendation has been made to follow the Findable, Accessible, Interoperable, Reusable (FAIR) principles. Without applying appropriate data exchange standards with domain-relevant content standards and accessible rich metadata that uses applicable terminologies, interoperability is burdened by the need for transformation and/or mapping. These obstacles to interoperability limit the findability, accessibility and reusability of data, thus diminishing its value and making it impossible to adhere to FAIR principles. One effort to standardize data collection has been through common data elements (CDEs). CDEs are data collection units comprising one or more questions together with a set of valid values. Some CDEs contain standardized terminology concepts that define the meaning of the data, and others include links to unique terminology concept identifiers and unique identifiers for each CDE; however, usually CDEs are defined for specific projects or collaborations and lack traceable or machine readable semantics. While the name implies that these are 'common', this has not necessarily been a requirement, and many CDEs have not been commonly used. The National Institutes of Health (NIH) CDEs are, in fact, a conglomerate of CDEs developed in silos by various NIH institutes. Therefore, CDEs have not brought the anticipated benefit to the industry through widescale interoperability, nor is there widespread reuse of CDEs. Certain institutes in the NIH recommend, albeit do not enforce, institute-specific preferred CDEs; however, at the NIH level a preponderance of choice and a lack of any overarching harmonization of CDEs or consistency in linking them to controlled terminology or common identifiers create confusion for researchers in their efforts to identify the best CDEs for their protocol. The problem of comparing data among studies is exacerbated when researchers select different CDEs for the same variable or data collection field. This manuscript explores reasons for the disappointingly low adoption of CDEs and the inability of CDEs or other clinical research standards to broadly solve the interoperability and data sharing problems. Recommendations are offered for rectifying this situation to enable responsible data sharing that will help in adherence to FAIR principles and the realization of Learning Health Systems for the sake of all of us as patients.

Calcium-mediated parathyroid hormone suppression to assess progression of secondary hyperparathyroidism during treatment among incident dialysis patients.

CONTEXT: Parathyroid gland function is affected adversely by tissue hyperplasia and gland enlargement in hyperparathyroidism. OBJECTIVE: We examined the effects of 2 treatment strategies on the progression of secondary hyperparathyroidism using measurements of the nonsuppressible component of calcium-regulated PTH secretion as an index of parathyroid mass. DESIGN, SUBJECTS, AND INTERVENTION: In this randomized, open-label study, subjects managed with hemodialysis for >3 but <12 months before entering the trial (mean, 7.2 months) who had baseline plasma PTH levels >300 pg/mL received cinacalcet and low-dose vitamin D sterols (Cin-D, n = 153) or larger, varying doses of calcitriol, or other vitamin D analogs (Flex-D, n = 151). Study drug doses were adjusted periodically based on PTH and serum total calcium determinations. MAIN OUTCOME MEASURES: The exploratory endpoint was calcium-regulated PTH release, assessed using a standardized PTH suppression test before and after 52 weeks of treatment and 4 weeks after withdrawing treatment. PTH and serum total calcium were measured before hemodialysis using high-calcium (3.5 mEq/L or 1.75 mmol/L) dialysate and after 150 and 180 minutes. RESULTS: Mean (95% confidence interval) nonsuppressible calcium-regulated PTH release at baseline did not differ between Cin-D, 33.4% (25.9%, 40.9%), and Flex-D, 28.1% (23.2%, 32.9%). Corresponding values after 52 weeks of treatment were 34.3% (29.7%, 38.9%) and 42.0% (32.7%, 51.3%), not significant, and did not change measurably in either group when reevaluated 4 weeks after treatments were withdrawn. CONCLUSION: Disease progression over 12 months was not documented using a PTH suppression test in this population. Calcium-mediated PTH suppression was maintained fully, however, in Cin-D despite reductions in serum total calcium concentration, whereas values did not increase in Flex-D despite substantial increases in serum calcium.

"Real-World" use of cinacalcet for managing SHPT in different European countries: analysis of data from the ECHO observational study.

AIMS: The pan-European ECHO observational study evaluated cinacalcet in adult dialysis patients with secondary hyperparathyroidism (SHPT) in "real-world" clinical practice. A sub-analysis compared data for 7 European countries/country clusters: Austria, CEE (Czech Republic and Slovakia), France, Italy, Netherlands, Nordics (Denmark, Finland, Norway, and Sweden), and the UK/Ireland. METHODS: Data on serum intact parathyroid hormone (iPTH), phosphorous, calcium, as well as the usage of cinacalcet, active vitamin D analogues and phosphate binders were compared. RESULTS: 1,865 patients (mean age 58 years) were enrolled: median baseline iPTH levels ranged from 605 pg/ml in Austria to 954 pg/ml in the UK/Ireland. After ~1 year of cinacalcet, median iPTH reductions from baseline ranged from 38% in the UK/Ireland to 58% in the Netherlands. The proportion of patients achieving NKF/K-DOQITM iPTH targets (150 - 300 pg/ml) at Month 12 ranged from 14% in the UK/Ireland to 40% in CEE. In general, use of sevelamer decreased, while use of calcium-based phosphate binders increased, during cinacalcet treatment. Vitamin D changes were more variable. CONCLUSION: The iPTH level at which cinacalcet is initiated in clinical practice differs considerably among different countries: where cinacalcet was started at a lower iPTH level this resulted in better achievement of serum iPTH targets.

Contribution of skin biometrology to the diagnosis of the Ehlers-Danlos syndrome in a prospective series of 41 patients.

BACKGROUND/PURPOSE: The diagnosis of the Ehlers-Danlos syndrome (EDS) is primarily clinical. Clinical signs result from modifications of the rheological properties of the skin: thickness, extensibility and hydration. Our main objective was to demonstrate what skin biometry can contribute to the diagnosis and evaluation of the different types of EDS. METHODS: Forty-one patients clinically diagnosed with EDS were paired by age and sex to 41 healthy subjects with no known dermatologic disease, in particular connective tissue diseases. We measured skin thickness, extensibility, hydration and sebum secretion by skin ultrasonography, use of a Cutometer, a Corneometer and a Sebumeter. RESULTS: The skin is thinner in all three disease types (classical, hypermobility and vascular). It is more extensible only in the classical type, and more hydrated and fatty in the hypermobility type. CONCLUSION: Non-invasive measurement of skin thickness and elasticity are quantitative parameters that can be used to better diagnose EDS. Moreover, the sebaceous rate can help to diagnose the hypermobility type whereas the immediate retraction distinguishes the classical form from vascular and hypermobile types.

Two treatment methods for stormwater sediments--pilot plant and landfarming--and reuse of the treated sediments in civil engineering.

The aim of this research was to present a pilot plant for the treatment of stormwater sediments and to compare the decontamination rate to that obtained by landfarming. The possibilities for reuse of the treated sediments in civil engineering are also studied. Four sediments from retention/infiltration ponds or from street sweeping were studied. In each case organic matter (OM), total hydrocarbons (TH) and polycyclic aromatic hydrocarbons (PAH) were measured. Geotechnical tests were carried out to evaluate the reuse possibilities of the treated sediments. Treatment by means of the pilot plant was efficient at reducing TH and PAH concentrations: THs were reduced by 53-97% and PAHs were decreased by 60-95%. By comparison, a reduction of 45-75% in TH concentration is obtained with landfarming, whereas there is no significant decrease in PAHs. Furthermore, geotechnical tests showed that the treated fractions from the pilot plant can be reused as road embankments and as a capping layer. These results are most encouraging and show that stormwater sediments can valuably be reused after treatment in a pilot plant. Landfarming is less efficient but this technique could be used as a pretreatment in the case of high TH pollution.

Reduction of sediment micro-pollution by means of a pilot plant.

Solutions need to be found to manage polluted (organic matter, trace elements, hydrocarbons and PAHs) stormwater sediments while complying with stringent economic and environmental requirements. The cost of transport is a relatively large part of the treatment cost for such sediments, hence the development of a pilot unit that could provide their in situ treatment. Seven stormwater sediments were treated by means of the ATTRISED pilot plant, based on sieving and attrition. The objective is to apply a treatment procedure by which as much clean material as possible is recovered, while the pollutants are concentrated in a small volume ready for final destruction or isolation from the environment. Application of the attrition process serves to remove fine particles and contaminants from the surface of sediments and hydrocyclone separations allow to isolate fine contaminated particles (< 60 microm). The results show that particle size separations coupled to an attrition step allow decontamination efficiencies of 76% and 70% for street sweeping and pond sediments, respectively. Although the experiments were carried out on stormwater sediments, all kinds of sediments may be treated by the ATTRISED pilot plant if the mean particle size is greater than 60 microm.