Clinical Trials in Japan-New GCP

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Simultaneous Test for Superiority and Noninferiority Hypotheses in Active-Controlled Clinical Trials∗

The primary objective of the dose-escalation trial for NGX267 was to estimate the maximally tolerated dose (MTD) and to gather detailed clinical and pharmacokinetic observations near the MTD. The MTD was defined based on the weighted average of moderate and severe adverse events. An adaptive design was employed to concentrate dosage assignments at or near the MTD. Favoring the acquisition of data near the MTD, at the expense of information at lower dosage levels, resulted in a shorter trial and no loss of the type of information required to inform subsequent studies where larger normal volunteer or patient samples are evaluated.     

Clinical Trials in Peking Union Medical College Hospital

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Special Issue on Active Controlled Clinical Trials—Guest Editor's Note

Limiting dilution assays (LDA) are used to estimate an unknown cell fraction of interest within a sample. This paper discusses a method for designing an LDA using the distribution of the cell fraction of interest, examining three different design approaches: geometric progression, equally spaced log, and equiprobability. Two common estimation methods, minimum chi-square and maximum likelihood, also are investigated. These designs and estimation methods, coupled with varying numbers of wells per dilution and dilutions per design, are compared quantitatively through computer simulation. Performance measures computed were mean relative bias and mean squared error.     

Validation Testing in Thorough QT/QTc Clinical Trials∗

Bioequivalence and clinical equivalence can be claimed based on the two one-sided test approach or the confidence interval approach. Consequently the power function of the equivalence test can be derived from either noncentral t-distribution or central t-distribution. The sample size is then determined from the power function either by numerical method or closed formulas. In this paper, we propose a simple formula for sample size calculation based on central t-distribution. The proposed formula has better properties than those currently available and it can be easily applied in all equivalence studies.     

Lyophilizer Leak Rate Testing – An Industry Survey and Best Practice Recommendation

The vacuum integrity of freeze dryers is critical for attaining adequate process control and maintaining confidence in sterility assurance which is key for the manufacture of sterile pharmaceutical products. Although discussions on the topic have been published, there is no industry standard established that is based on empirical data or that has a justifiable scientific rationale. This article provides a review of the scientific literature in the public domain and most importantly, a perspective from 14 Pharmaceutical companies on the leak rate specifications commonly used in industry. Using this information we recommend a best practice for the lyophilizer leak rate test which includes detailing necessary preparation activities following Steam-In-Place (SIP) sterilization, defining a period of stabilization to eliminate pressure and temperature fluctuations and details of the test conditions and the test period. We conclude that for routine manufacturing practice the operational leak rate should not exceed 20 µbar L/s and we provide additional guidance for large volume and older lyophilisation equipment.     

Comparisons of Serum Infliximab and Antibodies-to-Infliximab Tests Used in Inflammatory Bowel Disease Clinical Trials of Remicade®

Monitoring infliximab (IFX) concentrations and antibodies-to-IFX (ATI) titers during inflammatory bowel disease treatment may allow more informed decisions in assessing exposure/response and determining appropriate dosing. To aid in interpreting results from different commercial tests in the context of Janssen’s published Remicade® results, the reliability of Janssen’s IFX and ATI assays was compared with commercial assays from KU Leuven, Sanquin, Dynacare, and LabCorp. Test results were independently reported to Janssen. All assays were tested for specificity, selectivity, and precision. ATI assays were evaluated for sensitivity, drug interference, and potential interference of tumor necrosis factor-alpha (TNF-α). IFX assays were specific, accurate, and reproducible. Intra-class correlation of Janssen IFX assay results with those from KU Leuven, Sanquin, Dynacare, and LabCorp were 0.960, 0.895, 0.931, and 0.971, respectively. ATI titers >10 interfered with IFX assessment in all IFX assays, whereas TNF-α (≤50 ng/mL) did not interfere with IFX detection in any assay. ATI assays specifically and reproducibly detected ATI. Janssen, Sanquin, and LabCorp ATI methods were more resistant to IFX interference than Dynacare and KU Leuven, which were affected by IFX concentrations at ≥2 μg/mL. TNF-α (<5 ng/mL) did not interfere with ATI detection. Strong agreement was observed between Janssen’s IFX and ATI assays and the diagnostic service provider assays. Our study results indicate that all four commercially available assays are suitable for therapeutic drug monitoring of IFX. The substantial agreement reported here between the comparator assays and the Janssen drug-tolerant assay provides support to clinicians in their use of these commercial assays, and for understanding their patients’ IFX and ATI results relative to published data from clinical studies of Remicade.     

Partnerships and pathways of dissemination: The National Institute on Drug Abuse—Substance Abuse and Mental Health Services Administration Blending Initiative in the Clinical Trials Network

Since 2001, the National Drug Abuse Treatment Clinical Trials Network (CTN) has worked to put the results of its trials into the hands of community treatment programs, in large part through its participation in the National Institute on Drug Abuse—Substance Abuse and Mental Health Services Administration Blending Initiative and its close involvement with the Center for Substance Abuse Treatment's Addiction Technology Transfer Centers. This article describes (a) the CTN's integral role in the Blending Initiative, (b) key partnerships and dissemination pathways through which the results of CTN trials are developed into blending products and then transferred to community treatment programs, and (c) three blending initiatives involving buprenorphine, motivational incentives, and motivational interviewing. The Blending Initiative has resulted in high utilization of its products, preparation of more than 200 regional trainers, widespread training of service providers in most U.S. States, Puerto Rico, and the U.S. Virgin Islands and movement toward the development of Web-based implementation supports and technical assistance. Implications for future directions of the Blending Initiative and opportunities for research are discussed.     

What knowledge and skills are essential for specialists in Clinical Pharmacology and Therapeutics? Results of a Delphi study

AIMS: To identify the knowledge and skills that should be considered essential for specialists in Clinical Pharmacology and Therapeutics (CPT) with a commitment to the National Health Service (NHS). METHODS: A Delphi study using a sample of current specialists. RESULTS: Members of the expert panel (20 in all, representative of the Clinical Section membership) identified 78 statements for consideration, in four domains (core of knowledge, therapeutic skills, educative skills, and investigative skills), of which 58 (74.4%) were accepted by more than two-thirds of respondents. Of these, 35 were knowledge items, whereas 23 were skills (11 therapeutic, 4 educative and 8 investigative). The large majority (79.3%) of these statements were endorsed by at least four out of five panel members. CONCLUSIONS: Despite the varied work patterns and responsibilities of specialists in CPT, it is possible to identify a core of knowledge and skill that most consider essential for the delivery of their commitment to the NHS. The findings will provide NHS Trusts with a clear idea of what they can expect from these specialists, and will act as a checklist for specialists themselves to direct their Continuing Professional Development within the consultant appraisal process. The results also describe a curriculum for continuing education in CPT, which the BPS Clinical Section can use to develop information resources and training opportunities.     

On the Commonly Used Design and Statistical Considerations in Double Blind,Potentially Unblind,and Open‐Label Clinical Trials

In clinical trials, parallel group designs, such as placebo‐controlled trials or active‐controlled trials, are commonly used. The study design in comparative clinical trials to address the intended objective is vital to the interpretation of the trial results. If inappropriate study design are employed, they not only cannot answer the intended clinical hypothesis, but they can also impose adverse effects on the collection of efficacy and safety data that may further be compounded by observable and unobservable baseline data. Documentation and interpretation of the outcomes need to be carefully considered. It is well known that various sources of biases can arise during the course of the trial, for instance, design bias, operational bias, analytical bias, methodological bias, interpretation bias, and documentation bias. As a result of such biases, the accuracy and precision of the treatment effect estimate may be severely compromised, depending on the design considered. In this article, commonly used study designs for comparative clinical trials are described. Statistical considerations with various designs, the concept of robustness of statistical findings, and statistical evidence will be discussed in light of the blinding, potential unblinding, and open‐label designs.     

Applications of Breath Gas Analysis in Addiction Medicine—Preliminary Results

Information concerning types and frequencies of pretreatment drug abuse, obtained by interview from 11,380 patients included in the first two years (June 1969-June 1971) of the NIMH-TCU Drug Abuse Reporting Program, were examined with respect to patterns of usage. Twenty-eight patterns were defined, involving various combinations of drugs used and frequencies of use. The results indicated that the most frequent drug-abuse pattern in this patient sample, accounting for 28% of the entire sample, was the daily or weekly use of heroin with no other drugs. The daily or weekly use of heroin with cocaine, with marihuana, and with both cocaine and marihuana were also frequently observed patterns, and combined with the heroin-only pattern, they characterized the majority of all the patients. The most common patterns reported by the remainder of the patients were of poly-drug use, typically involving marihuana, amphetamines, and barbiturates, as well as heroin and cocaine.     

Best Practices for Drug Substance Stress and Stability Studies During Early-Stage Development Part I—Conducting Drug Substance Solid Stress to Support Phase Ia Clinical Trials

Regulatory guidances for drug stability testing during early development stages lack specifics. Consequently, companies either conduct more stability studies than necessary just to avoid regulatory questions or perform insufficient stability work resulting in regulatory questions and delays in drug development. Hence, there exist a pressing need and a great opportunity for pharmaceutical companies to share drug stability testing practices, rationales, and regulatory experiences for the early stages of development. This paper describes a quick, streamlined solid stress practice to support drug development from pre-clinical to Phase Ia Clinical Trials. By subjecting a few grams of drug substance to high temperature and high humidity (e.g., 70?°C/75?% RH, in open and closed containers, for three weeks) and to the ICH Q1B confirmatory photostability testing condition, the initial DS retest period and the initial shelf life of powder for oral solution can be reliably extrapolated, and a bulk packaging choice is made. In addition, the solid stress results can be used for multifaceted purposes. The solid stress practice offers a quick turnaround in obtaining adequate stability information for new drug development and achieves an optimum balance between risk and cost for Phase Ia clinical development.     

Challenges in orthopedic surgical randomized trials:design and analysis

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In vitro and in vivo effects of cadmium on cholinesterases in Nile tilapia fingerlings: implications for biomonitoring aquatic pollution

Effects of cadmium on in vitro and in vivo cholinesterase (ChE) activities of brain and muscle tissues of Oreochromis niloticus fingerlings were evaluated, considering its potential use in biomonitoring tropical water pollution. Results show that in vitro ChE activities were depressed significantly by millimolar concentration ranges of Cd²⁺. The IC₅₀ values of Cd²⁺ on in vitro ChE activity in brain and muscle tissues were 1.56 and 4.31 mM, respectively. Exposure of fish to environmentally relevant concentrations of Cd²⁺ (5–30 μg l^−l) for 28 days evoked only a transient inhibition (21–34%) of in vivo ChE activities. Prior exposure and co-exposure of fish to 15 μg l⁻¹ of Cd²⁺ enhanced the extent of inhibition of ChE levels induced by the organophosphorous insecticide chlorpyrifos. As high concentrations of cadmium have the potential to depress ChE activities, monitoring of metal levels in water bodies with suspected high levels of metal inputs is necessary to accurately interpret the fish ChE inhibition data in relation to insecticide contaminations.     

Bioaccumulation and physiological effects of mercury in Pteris vittata and Nephrolepis exaltata

Anatomical, histochemical and biochemical approaches were used to study mercury uptake and phytotoxicity as well as anti-oxidative responses in two species of ferns [Chinese brake fern (Pteris vittata) and Boston fern (Nephrolepis exaltata)], grown in a hydroponic system. The roots of both cultivars accumulated large amounts of mercury, but exhibited limited mercury translocation to shoots. Mercury exposure led to more pronounced phytotoxicity accompanied by stronger oxidative stress in the shoots of P. vittata than in N. exaltata. N. exaltata established a more effective anti-oxidative system against mercury-induced oxidative stress than did P. vittata. The activity of anti-oxidative enzymes (superoxide dismutase, catalase and glutathione reductase) increased. The reduced ascorbate (ASA) and oxidized ascorbate (DHA) are regulated. Mercury exposure led to an increase in the concentration of glutathione (GSH) in both fern species. The present study suggests that N. exaltata is more tolerant to mercury exposure than P. vittata, which has been also reported to be more tolerant to arsenic exposure. N. exaltata may thus have potential for phytostabilization of soils or phytofiltration of waste water contaminated with mercury.