Regulatory Acceptance Criteria Research Articles

Comprehensive performance evaluation of ligand-binding assay-LC-MS/MS method for co-dosed monoclonal anti-SARS-CoV-2 antibodies (AZD7442).

Aims: AZD7442 is a combination SARS-CoV-2 therapy comprising two co-dosed monoclonal antibodies. Materials & methods: The authors validated a hybrid ligand-binding assay-LC-MS/MS method for pharmacokinetic assessment of AZD7442 in human serum with nominal concentration range of each analyte of 0.300-30.0μg/ml. Results: Validation results met current regulatory acceptance criteria. The validated method supported three clinical trials that spanned more than 17months and ≥720 analytical runs (∼30,000 samples and ∼3000 incurred sample reanalyses per analyte). The data generated supported multiple health authority interactions, across the globe. AZD7442 (EVUSHELD) was approved in 12 countries for pre-exposure prophylaxis of COVID-19. Conclusion: The results reported here demonstrate the robust, high-throughput capability of the hybrid ligand-binding assay-LC-MS/MS approach being employed to support-next generation versions of EVUSHELD, AZD3152.

360 Assessment of Pedicle Screw Placement Accuracy Utilizing a Novel Augmented Reality and Artificial Intelligence Surgical Guidance System

INTRODUCTION: The integration of artificial intelligence (AI) and augmented reality (AR) technologies in spine navigation has the potential to minimize pedicle screw misplacement, decrease radiation exposure, and improve procedural efficiency, addressing some of the challenges associated with spinal instrumentation. METHODS: Sixty lumbosacral pedicle screws were placed by 4 Orthopedics surgeons in 6 cadavers using the AR/AI surgical navigation system. Two CT intraoperative scans (before and after screw placement) of the cadaveric specimens were obtained for the study to measure the 3D positional and angular discrepancies between virtual and real screws. The validation procedure consisted of 3 steps: (1) automatic registration and 3D coordinate transformation, where the preop CT scan was aligned with the postop scan to determine the virtual screw 3D positions and orientations in postop scan; (2) analysis of the postop scan to determine the real screw 3D positions and orientations as they appeared in the scan volume; (3) automatic comparison between the 3D positions and orientations of the virtual and real screws. RESULTS: A one-sample t-test statistical analysis yielded a mean positional error of 2.16 mm ± 1.00 mm (99% CI: 1.81-2.49 mm), and a mean angular error of 1.49± 0.73° (99% CI: 1.25-1.74°). These results were independent of anatomical level, side, and surgeon. CONCLUSIONS: This study indicates that this AR/AI surgical guidance system provides mean positional and angular errors lower than 3.0 mm and 3.0° respectively, thus complying with FDA-required regulatory acceptance criteria. The system was FDA-cleared as a US 510k Orthopedic Stereotaxic Instrument.

In Vitro-In Vivo Correlations (IVIVC) for Predicting the Clinical Performance of Metronidazole Topical Creams Intended for Local Action.

The safety and efficacy of a generic medicine can be confirmed by demonstrating bioequivalence (BE) between the generic product and its reference listed drug (RLD) by measuring drug concentrations in the blood following administration. However, for topical dermatological products that are not absorbed into the systemic circulation, clinical trials in patients are required. The objective of this investigation was to use an in vitro method to predict in vivo performance by correlating in vitro release testing (IVRT) data with tape stripping (TS) data following the application of metronidazole (MTZ) creams to the skin of healthy human participants. Whereas IVRT is generally used to characterize the release of a drug from topical products across a synthetic membrane into a suitable receptor medium, TS involves the sequential removal of layers of stratum corneum (SC) with an adhesive tape to determine the amount of the drug in the skin. The resulting IVRT and TS data were correlated using the IVRT parameter of the apparent release constant (ARC), which is the slope obtained from the release rate profile, with the TS parameter of the area under the curve (AUC) obtained from a plot of the amount of drug per tape strip vs. the relative SC depth. A rank order relationship for these parameters was established for the reference and test products. A graph of AUC vs. ARC was plotted to establish a Level C in vitro-in vivo correlation (IVIVC). Although the ARC for T1 was slightly lower than that for the reference, the rank order was essentially consistent. A linear relationship was observed between the AUCs and ARCs. The equation derived was used to predict the AUCs for all the tested products based on their respective ARCs. The predicted AUC values based on the observed ARCs were similar to the observed AUCs. The lower and upper limits for the in vitro and in vivo parameters for BE were computed based on regulatory acceptance criteria. In order to predict BE from the IVRT studies, the values of the ARC should be between 30.50 and 47.67 when comparing test and reference cream products containing MTZ.

Development of In Vitro\u2013In Vivo Correlation for Upadacitinib Extended-Release Tablet Formulation

Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed for the treatment of several inflammatory diseases including rheumatoid arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral extended-release (ER) formulation administered once daily. The purpose of this study was to develop a level A in vitro–in vivo correlation (IVIVC) for upadacitinib ER formulation. The pharmacokinetics of four upadacitinib extended-release formulations with different in vitro release characteristics and an immediate-release capsule formulation of upadacitinib were evaluated in 20 healthy subjects in a single-dose, randomized, crossover study. In vivo pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were used to establish the IVIVC, and the fourth formulation was used for external validation. A non-linear IVIVC best described the relationship between upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute percent prediction errors (%PE) for upadacitinib Cmax and AUC were less than 10% for all three formulations used to establish the IVIVC, as well as for the %PE for the external validation formulation and the overall mean internal validation. Model was cross-validated using the leave-one-out approach; all evaluated cross-validation runs met the regulatory acceptance criteria. A level A IVIVC was successfully developed and validated for upadacitinib ER formulation, which meets the FDA and EMA regulatory validation criteria and can be used as surrogate for in vivo bioequivalence.

Development, validation and application of a novel HPLC-MS/MS method for the measurement of minocycline in human plasma and urine

New treatments are urgently required to treat infections caused by multi-drug resistant Acinetobacter baumanni,. To address this need, a new formulation of Minocin®, (minocycline for injection) has been developed that allows for higher doses of minocycline to be administered. Phase 1 clinical trials were conducted in healthy volunteers to assess the safety and pharmacokinetics (PK) of this new formulation at higher doses. In order to generate PK data, novel, selective and simple HPLC-MS/MS based assays were developed and validated for the determination of minocycline (MC) in human plasma and urine. The respective working ranges were 0.05 to 30 mg/L and 0.1 to 30 mg/L. Removal of endogenous proteins with trichloroacetic acid was used as a simple means of extracting MC from the samples. An analogue, tetracycline was used as the internal standard (IS). Chromatographic separation, including that of MC from its 4-epimer (4-EMC), was achieved on a Waters XBridge BEH C18 column (50 x 4.6 mm ID, 5 μm) with gradient elution. The mobile phases comprised water containing 5 mM ammonium formate at a pH of 2.5, and methanol containing 5 mM ammonium formate. The internal standard (IS) was tetracycline, a structural analogue of minocycline.The methods were fully validated and met regulatory acceptance criteria for intra-run and inter-run accuracy and precision, carryover, dilution integrity and matrix effects. Mean extraction recoveries ranged between 64.3% and 84.6% for MC and 64.3% for the IS. There was no significant ion suppression or enhancement for MC or the IS. The validated assays were successfully applied to 1423 plasma and 689 urine samples from a Phase 1 clinical study.There was no evidence of instability, or significant interconversion between MC and 4-EMC, in stored clinical samples, spiked plasma and urine samples, or their extracts, under various test conditions.

SHAKE-RoverD Framework for Nuclear Power Plants: A Streamlined Approach for Seismic Risk Assessment

A major challenge facing the nuclear energy industry is to remain competitive under current market conditions. Utility operators are searching for innovative methods to reduce nuclear power plant (NPP) operation and maintenance costs while complying with safety and reliability requirements. To support these goals, the authors suggest a streamlined approach that implements a conservative risk-informed method to reduce the costs of satisfying emergent regulatory requirements. As a streamlined approach, the Risk-informed Over Deterministic (RoverD) method was developed by some of the authors of the current paper to resolve the concerns associated with Generic Safety Issue 191 (GSI-191). The RoverD method is designed around U.S. Nuclear Regulatory Commission Regulatory Guide 1.174 (RG 1.174), which defines “risk-informed” regulation as comprising a blend of risk-based and deterministically based elements. This paper offers the Safety Hazard Analysis for earthquaKE (SHAKE)–RoverD (SHAKE-RoverD) methodology, an extension of the original RoverD methodology developed for GSI-191, to evaluate the impact of an increased seismic hazard on the performance of NPP protective systems. SHAKE-RoverD aims to reduce the cost required for developing, validating, and documenting detailed fragility curves in seismic probabilistic risk assessment by using deterministic fragility curves. The SHAKE-RoverD methodology assesses whether an increase in a seismic hazard would result in an unacceptable increase in NPP risk. If the conservative estimate of plant risk, computed by the streamlined approach, satisfies the regulatory acceptance criteria (e.g., Regulatory Guide 1.174), the plant likely would not need to make a design change (as long as defense in depth and adequate safety margin are satisfied); therefore, the use of streamlined methodology could lead to significant cost savings for the utility operator. Future work will advance SHAKE-RoverD and analyze risk management strategies based on this method.

Evaluation of Fast Neutron Fluence for Reactor Pressure Vessel Surveillance of Chashma Nuclear Power Plants Units 1 and 2

The energy-dependent neutron flux incident on surveillance capsule assemblies (SCAs) installed at the outer surface of the core barrel in two pressurized water reactors-Chashma Nuclear Power Plants Units 1 and 2 was evaluated. This safety study was made for the reactor pressure vessel surveillance program to determine the fast-neutron-induced radiation embrittlement of vessel materials in sections facing the core side and the upper weld positions. A total of 68 radiometric sensors were irradiated in each SCA of these two reactors, and dosimetry data were measured from radiometric sensors. Fast neutron flux (E > 1 MeV) was best estimated using the least-squares method by employing LSL-M2 package. Measured results were compared with the fast neutron flux calculated using MCNP5 at the base and weld metal sections of SCA. The results agreed within ±20% of each other in both reactors, which satisfy the regulatory acceptance criteria. Therefore, these results can be used in life assessment of reactors.

10 CFR 50.46c Rulemaking: A Novel Approach in Restating the LOCA Problem for PWRs

The U.S. Nuclear Regulatory Commission (NRC) is considering a rulemaking that would revise requirements in 10 CFR 50.46 [also known as the emergency core cooling system (ECCS) rule]. Experimental work sponsored by the NRC suggested that the current regulatory acceptance criteria on ECCS performance during design-basis accidents are actually nonconservative for higher-burnup fuel, that embrittlement mechanisms not contemplated in the original criteria exist, and that the 17% limit on oxidation is not adequate to preserve the level of ductility that the NRC originally deemed to be warranted for adequate protection. The new rule imposes new acceptance criteria and is expected to be in effect within this decade. An implementation plan was developed that will give individual plants up to 7 years with which to comply once the rule is amended, depending on the status of each plant's analysis of record, the effort involved, and existing analytical margin to the limits.The proposed rule may challenge U.S. light water reactor fleet operational flexibility and economics. Within the U.S. Department of Energy Light Water Reactor Sustainability Program, the Idaho National Laboratory is pursuing an initiative that is focused on industry applications using Risk-Informed Safety Margin Characterization (RISMC) tools and methods applied to issues that are of current interest to the operating fleet. The mission of RISMC is to provide cost-beneficial approaches to safety analysis by leveraging modern methods, augmented tools (a combination of existing and new), and repurposed data (existing, but used in a new way).

중수로 원자로건물 총누설감시계통 시험 중지에 따른 리스크 영향 평가

Wolsong Unit 2,3&4 has been performing a containment integrity test during power operation. This test could impact to the safe operation during test. If an accident occurs during pressure dropping phase, reactor trip can be delayed because of the increased pressure difference which causes a time delay to reach the trip set-point. On the contrary, if an accident occurs during pressure increasing phase, reactor trip could be accelerated because the pressure difference to the trip set-point decrease. Point Lepreau nuclear power plant, which installed GCLMS (Gross Containment Leakage Monitoring System) in 1990, has discontinued the test since 1992 due to these adverse effects. Therefore, we evaluated the risk to obviate the GCLMS test based on PWR's ILRT (Integrated Leak Rate Test) extension methodologies. The results demonstrate that risk increase rate is not high in case of performing only ILRT test at every 5 years instead of doing GCLMS test at every 1.5 years. In addition, the result shows that GCLMS test can be removed on a risk-informed perspective since risk increasement is in acceptable area of regulatory acceptance criteria.

Regulatory acceptance and use of 3R models for pharmaceuticals and chemicals: Expert opinions on the state of affairs and the way forward

Pharmaceuticals and chemicals are subjected to regulatory safety testing accounting for approximately 25% of laboratory animal use in Europe. This testing meets various objections and has led to the development of a range of 3R models to Replace, Reduce or Refine the animal models. However, these models must overcome many barriers before being accepted for regulatory risk management purposes. This paper describes the barriers and drivers and options to optimize this acceptance process as identified by two expert panels, one on pharmaceuticals and one on chemicals. To untangle the complex acceptance process, the multilevel perspective on technology transitions is applied. This perspective defines influences at the micro-, meso- and macro level which need alignment to induce regulatory acceptance of a 3R model. This paper displays that there are many similar mechanisms within both sectors that prevent 3R models from becoming accepted for regulatory risk assessment and management. Shared barriers include the uncertainty about the value of the new 3R models (micro level), the lack of harmonization of regulatory requirements and acceptance criteria (meso level) and the high levels of risk aversion (macro level). In optimizing the process commitment, communication, cooperation and coordination are identified as critical drivers.

Extended antigen sparing potential of AS03-adjuvanted pandemic H1N1 vaccines in children, and immunological equivalence of two formulations of AS03-adjuvanted H1N1 vaccines: results from two randomised trials

BackgroundPandemic influenza vaccine manufacturing capacity and distribution agility is enhanced through the availability of equivalent antigen-sparing vaccines. We evaluated equivalence in terms of immunogenicity between GlaxoSmithKline Vaccines’ A/California/7/2009 (H1N1)v-like-AS03 vaccines manufactured in Dresden (D-Pan), and Quebec (Q-Pan).MethodsIn two studies, 334 adults 18-60 years of age received 2 doses of D-Pan or Q-Pan containing 3.75 μg haemagglutinin antigen (HA) adjuvanted with AS03A administered 21 days apart, and 209 children 3-9 years of age received 1 reduced dose of D-Panor Q-Pan (0.9 μg HA) or Q-Pan (1.9 μg HA) with AS03B. Haemagglutination inhibition (HI) titres were assessed before and 21 days post-vaccination. HI persistence was assessed after 12 months in adults and 6 months in children.ResultsPre-defined criteria for immunological equivalence of Q-Pan versus D-Pan were achieved in both populations. After one vaccine dose, ≥97.6% of adults and children had HI titres ≥1:40, with increases in titre ≥25.7-fold. CHMP and CBER regulatory acceptance criteria for influenza vaccines were exceeded by all groups in both studies at Day 21. In adults,the percentage with HI titres ≥1:40 at Month 12 was 82.9% (Q-Pan) and 84.0% (D-Pan). In children, the percentages at Month 6 were 75.3.3% (Q-Pan0.9), 85.1% (D-Pan0.9) and 79.3% (Q-Pan1.9). Safety profile of the study vaccines was consistent with previously published data.ConclusionTwo studies indicate that A/California/7/2009 (H1N1)v-like HA manufactured at two sites and combined with AS03 are equivalent in terms of immunogenicity in adults and children and highly immunogenic. Different HA doses elicited an adequate immune response through 180 days post-vaccination in children 3-9 years of age.Trial registrationClinicalTrials.gov: NCT00979407 and NCT01161160.

Generics, chemisimilars and biosimilars: is clinical testing fit for purpose?

The effectiveness and safety of generic drugs are backed by sound physicochemical control and regulatory bioequivalence acceptance criteria. Statistical testing of bioequivalence, comparing the pharmacokinetic profiles of the test and reference products, was made possible by modern drug assays. When the pharmacokinetic profile correlates with the dose, such comparisons show assay sensitivity and readily detect differences in dose. For large biological molecules, different manufactured batches cannot be validated using pharmacokinetic data alone. For these biosimilars, there is a three-stage assessment of pharmaceutical quality, laboratory testing and clinical data. This approach has also been applied to certain chemical products, termed 'chemisimilars', which have variable or complex synthesis of the active substance, or complex formulation, or a complex delivery device. Although there may be no detectable difference between the test and reference on clinical testing, many of the outcome measures are insensitive to even large differences in dose. For testing to be fit for purpose it should distinguish important dose differences, but many clinical tests of chemisimilars and biosimilars do not. As pharmacokinetic and pharmacodynamic technology advances, the trend of replacing dose-insensitive clinical trial data with equivalence tests that show assay sensitivity can be expected to continue.

Flexibility of interval between vaccinations with AS03A-adjuvanted influenza A (H1N1) 2009 vaccine in adults aged 18–60 and >60 years: a randomized trial

BackgroundFlexibility of vaccination schedule and lower antigen content can facilitate pandemic vaccine coverage. We assessed the immune response and safety of AS03-adjuvanted A/California/7/2009 H1N1 pandemic vaccine containing half of the registered adult haemagglutinin (HA) antigen content, administered as a two-dose schedule at intervals of 21 days or 6 months in both young and elderly adults.MethodsIn this open-label randomized trial, healthy adults aged 18–60 years (N = 163) and >60 years (N = 143) received AS03A-adjuvanted A/California/7/2009 H1N1 vaccine containing 1.9 μg HA on Day 0. A second dose was given on Day 21 (n = 177) or Day 182 (n = 106). Haemagglutination-inhibition (HI) antibody responses were analyzed on Days 0, 21, 42, 182, 364 and additionally on Day 203 for subjects vaccinated on Day 182. Solicited and unsolicited adverse events were recorded.ResultsThe HI antibody response in both age strata 21 days after the first dose met and exceeded all regulatory acceptance criteria although the results suggested a lower response in the older age stratum (geometric mean titres [GMTs] for HI antibodies of 420.5 for subjects aged 18–60 years and 174.4 for those >60 years). A second dose of AS03A adjuvanted A/H1N1/2009 vaccine induced a further increase in antibody titres and the response was similar whether the second dose was administered at 21 days (GMTs of 771.8 for 18–60 years and 400.9 for >60 years) or 6 months (GMTs of 708.3 for 18–60 years and 512.1 for >60 years) following the first dose. Seroprotection rates remained high at 6 months after one dose or two doses while at 12 months rates tended to be higher for the 6 month interval schedule (93.3% for 18–60 years and 80.4% for >60 years) than the 21 day schedule (82.3% for 18–60 years and 50.0% for >60 years). Reactogenicity/safety profiles were similar for both schedules, there was no evidence of an increase in reactogenicity following the second dose.ConclusionsThe results indicate that flexibility in the dosing interval for AS03A adjuvanted vaccine may be possible. Such flexibility could help to reduce the logistic stress on delivery of pandemic vaccination programmes.Trial registrationClinicalTrials.gov, NCT00975884

Immunological priming induced by a two-dose series of H5N1 influenza antigen, administered alone or in combination with two different formulations of AS03 adjuvant in adults: Results of a randomised single heterologous booster dose study at 15 months

One influenza pandemic preparedness strategy involves priming a population with a pre-pandemic subtype-specific vaccine and boosting the immunological response at the time of the pandemic with a strain-matched vaccine. In the current study, adults (n=469) randomised 15 months previously to receive an A/Indonesia/5/2005 (H5N1) influenza vaccine (3.75μg haemagglutinin antigen [HA]) administered alone or in combination with an oil-in-water emulsion based Adjuvant System containing 11.86mg (AS03A) or 5.93mg (AS03B) tocopherol per dose, received one booster dose of A/turkey/Turkey/1/2005 (H5N1) vaccine (3.75μg HA) with or without AS03A. An anamnestic antibody response that met US regulatory acceptance criteria was observed 15 months after priming. Although superior immunogenicity of AS03-adjuvanted compared to unadjuvanted priming was not demonstrated, higher antibody titres which persisted longer were seen when both priming and boosting regimens were adjuvanted. This may affect duration of response or heterologous immunity. The booster vaccines had a clinically acceptable safety/reactogenicity profile after adjuvanted or unadjuvanted priming. This study has been registered at www.clinicaltrials.govNCT00771615.

Immunogenicity and safety of AS03-adjuvanted H1N1 pandemic vaccines in children and adolescents

Vaccines with acceptable efficacy profile against the H1N1 A/California/7/2009 virus are needed for use in children. The two studies presented here evaluated the immunogenicity and the reactogenicity/safety of A/H1N1/2009 vaccines containing either 3.75μg haemagglutinin antigen (HA) and AS03A-adjuvant (3.75μg HA/AS03A study) (N=210 [53, 57 and 100 in the 3–5, 6–9 and 10–17 years age strata, respectively]) or 1.9μg HA and AS03B-adjuvant (1.9μg HA/AS03B study) (N=244 [61, 65 and 118 in the 3–5, 6–9 and 10–17 years age strata, respectively]), given as two-dose series. Although the haemagglutination inhibition antibody titres were higher in the 3.75μg HA/AS03A study, both vaccine dosages were highly immunogenic and exceeded regulatory acceptance criteria after the first and the second doses. Seroprotection rates reached 100% and seroconversion rates ranged from 98.2% to 99.1% after each dose of both vaccine dosages. Geometric mean titres increased from 456.5 to 1538.5 and from 297.9 to 1106.7 between the first and the second doses in the 3.75μg HA/AS03A study and the 1.9μg HA/AS03B study, respectively. Despite an observed slight increase of the reactogenicity following the second dose in the 3.75μg HA/AS03A study, the vaccines safety profiles were considered clinically acceptable. In conclusion, both dosages of the AS03-adjuvanted A/H1N1/2009 pandemic influenza vaccines were highly immunogenic and well-tolerated in children and adolescents.

Lessons Learned from the U.S. Nuclear Regulatory Commission’s Digital System Risk Research

For the past several years, the U.S. Nuclear Regulatory Commission and its contractors have been actively engaged in research to determine the capabilities and limitations of the state of the art of digital systems risk and reliability modeling. This program was developed to assess the capabilities of various modeling methods and to develop regulatory acceptance criteria for the use of digital system risk and reliability modeling in risk-informing digital system reviews. The program investigated both traditional and advanced modeling methods for the evaluation of digital system risk and reliability in the context of including these methods in current generation probabilistic risk assessments (PRAs). The methods investigated included traditional event tree/fault tree analysis, Markov modeling, and dynamic flow graph methodology. As part of the investigation into the capabilities of these methods, we have also reviewed the availability, capability, and practicality of the needed supporting data and analysis methods, including failure mode identification, data generation methods, and uncertainty analysis. The review indicated that for some digital systems traditional PRA modeling methods may be appropriate but that a number of potential issues exist that must be carefully evaluated in modeling these systems. Both the traditional and advanced modeling methods review found that the order of component failures can be important and that simulation either as part of the reliability model or as part of the supporting analysis is needed to determine the effects of combinations of component failures and the timing of digital system failures. Finally, the research showed that better data and models of fault-tolerant features of digital systems and software are needed to support more complete and accurate modeling of digital instrumentation and control for use in nuclear power plant PRAs.

A phase II, open-label, multicentre study to evaluate the immunogenicity and safety of an adjuvanted prepandemic (H5N1) influenza vaccine in healthy Japanese adults

BackgroundPromising clinical data and significant antigen-sparing have been demonstrated for a pandemic H5N1 influenza split-virion vaccine adjuvanted with AS03A, an α-tocopherol-containing oil-in-water emulsion-based Adjuvant System. Although studies using this formulation have been reported, there have been no data for Japanese populations. This study therefore aimed to assess the immunogenicity and tolerability of a prepandemic (H5N1) influenza vaccine adjuvanted with AS03A in Japanese adults.MethodsThis open-label, single-group study was conducted at two centres in Japan in healthy Japanese males and females aged 20-64 years (n = 100). Subjects received two doses of vaccine, containing 3.75 μg haemagglutinin of the A/Indonesia/5/2005-like IBCDC-RG2 Clade 2.1 (H5N1) strain adjuvanted with AS03A, 21 days apart. The primary endpoint evaluated the humoral immune response in terms of H5N1 haemagglutination inhibition (HI) antibody titres against the vaccine strain (Clade 2.1) 21 days after the second dose. Ninety five percent confidence intervals for geometric mean titres, seroprotection, seroconversion and seropositivity rates were calculated. Secondary and exploratory endpoints included the assessment of the humoral response in terms of neutralising antibody titres, the response against additional H5N1 strains (Clade 1 and Clade 2.2), as well as the evaluation of safety and reactogenicity.ResultsRobust immune responses were elicited after two doses of the prepandemic influenza vaccine adjuvanted with AS03A. Overall, vaccine HI seroconversion rates and seroprotection rates were 91% 21 days after the second vaccination. This fulfilled all regulatory acceptance criteria for the vaccine-homologous HI antibody level. A substantial cross-reactive humoral immune response was also observed against the virus strains A/turkey/Turkey/1/2005 (Clade 2.2) and A/Vietnam/1194/2004 (Clade 1) after the second vaccine administration. A marked post-vaccination response in terms of neutralising antibody titres was demonstrated and persistence of the immune response was observed 6 months after the first dose. The vaccine was generally well tolerated and there were no serious adverse events reported.ConclusionsThe H5N1 candidate vaccine adjuvanted with AS03A elicited a strong and persistent immune response against the vaccine strain A/Indonesia/5/2005 in Japanese adults. Vaccination with this formulation demonstrated a clinically acceptable reactogenicity profile and did not raise any safety concerns in this population.Trial registrationClinicaltrials.gov NCT00742885

Use of risk measures in design and licensing of future reactors

Use of information and insights from probabilistic risk assessments (PRAs) in nuclear reactor safety applications has been increasing by the nuclear industry and the regulators, both domestically and internationally. This is a desirable trend, as PRAs have demonstrated capability to improve safety and operational flexibility beyond that provided through deterministic approaches alone. But there can be potential pitfalls. The limitations of risk assessment technology can be lost through approaches that rely heavily on quantitative PRA results (referred to as risk measures in this paper), because of the unambiguous but potentially misleading message that can be delivered by risk-based numbers. This is particularly true for future reactors, where PRAs are used during the design and licensing processes. For these applications, it is important to ensure that the actual, de facto, or even perceived use of risk measures in the context of either regulatory or design acceptance criteria is avoided. While the issues discussed here can have a significant influence on design certification or combined license applications for future reactors, they can also have secondary impacts on currently operating reactors.

Evaluation of Bioequivalence for Highly Variable Drugs with Scaled Average Bioequivalence

Bioequivalence studies are performed to demonstrate in vivo that two pharmaceutically equivalent products (in the US) or alternative pharmaceutical products (in the EU) are comparable in their rate and extent of absorption. By definition, for highly variable drugs (HVDs), the estimated within-subject variability is >30%. HVDs often fail to meet current regulatory acceptance criteria for average bioequivalence (ABE). The determination of the bioequivalence of HVDs has been a vexing problem since the inception of the current regulations. It is of concern not only to the generic industry but also to the innovator industry. This article reviews the definition of HVDs, the present regulatory recommendations and the approaches proposed in the literature to deal with the bioequivalence problems of HVDs. The approach of scaled ABE (SABE) is proposed as the most adequate procedure to solve the problem. It is demonstrated that SABE has firm theoretical foundations. In fact, statistical tests similar to SABE are used in various fields, such as psychology and quality control. Algorithms and numerical examples are presented to calculate SABE from the data in conventional two-period and replicate-design studies. The most important feature of SABE is that a fixed sample size is adequate to demonstrate bioequivalence regardless of within-subject variability. The conditions for reaching consistent regulatory decisions with SABE are discussed. The required sample size, for a given statistical power, depends on the regulatory criteria. Sample sizes with different criteria are demonstrated and compared with those arising from a recent informal US FDA proposal. Pragmatic considerations lead to modifications of the theoretical concept of SABE. Several modifications are proposed, including reference scaling, restriction on the estimated geometric mean ratios and possibly limiting SABE to only secondary bioequivalence metrics such as the maximum concentration. Each proposal has its own merit but is also a source of new controversy. Overall, the statistical evaluation of SABE is more complex than that of ABE, which means higher regulatory burden. Standardized open software could be very useful in this regard. A small program script is presented to calculate SABE confidence limits.

Error propagation in pesticide residue measurements estimated by computational simulations and inter-laboratory sample analysis

An assessment of the error associated with conventional pesticide residue analysis has been conducted based on computer simulations and inter-laboratory residue analysis. Computational simulations were conducted based on (i) typical performance and regulatory acceptance criteria of analytical methods, and (ii) field residue distributions. In addition, field samples with incurred residues were sent to different private laboratories and the results compared. The relative difference in pesticide residues obtained when samples from the same field or produce lot are analyzed at separate laboratories was used to quantify the uncertainty associated with residue analyses performed using common analytical technology, and methods that are in compliance with current regulatory requirements. The study showed that differences of > 100% are common and should be expected when samples from the same crop are analyzed at different laboratories. The results also suggest that the error within residue measurements can be particularly detrimental when a result is reported near the maximum residue limit (MRL).