Regulatory Definition Research Articles

ACOs, 3-Day Rule, Team Roles Are Top Issues

ACOs, 3-Day Rule, Team Roles Are Top Issues

Amphibole asbestos soil contamination in the U.S.A.: A matter of definition

Recent concerns surrounding asbestos exposure have extended from occupational settings into natural settings. These developments have caused us to examine the distribution of amphiboles, which are potential asbestiform minerals, within the soils of the U.S.A. Evaluation of mineralogical data from selected sand and/or silt fraction of soils from the USDA-NRCS National Cooperative Soil Survey database shows that soils in all states (except for Rhode Island) contain amphiboles. In 41 of the 50 states, 10% or more sampled pedons contain amphiboles. Overall, 4396 pedons out of the 34 326 pedons (about 13%) sampled in the U.S.A. contained amphiboles. Pedons containing amphiboles ranged from less than 1 to 49% of the pedons among all states. While amphibole asbestos deposits occur in mafic and ultramafic provinces, soil amphiboles occur evenly distributed across the U.S.A. The majority of the amphiboles found in the soils would likely not meet the mineralogical definition of asbestos (i.e., they would not have been derived from asbestiform amphiboles); however, the majority would likely meet a commonly used regulatory definition of a fiber (i.e., are over 5 μm in length with a greater than 3 to 1 aspect ratio). Based on the regulatory definition, 13% of soil pedons and 5% of soil horizons in the U.S.A. are “naturally contaminated.”

Implications Of The Risk-Based Capital Requirements Of Implicit Recourse In Asset Securitizations In The Banking Industry

<p class="MsoBodyText2" style="text-align: justify; line-height: normal; margin: 0in 0.5in 0pt;"><span style="font-size: 10pt; mso-bidi-font-style: italic; mso-bidi-font-size: 12.0pt;"><span style="font-family: Times New Roman;">We consider implications of the risk-based capital requirements of implicit recourse in asset securitizations. These implications include issues in finance such as risk management and contracting between counterparties. The first part of our analysis deals with asset securitizations where originating institutions provide investors with implicit recourse. We show that the risk-based capital requirements associated with the new regulatory definition of implicit recourse may discourage some banks from offering implicit recourse in their asset securitizations. This suggests that the new regulatory definition of implicit recourse may be a workable compromise between supervisory regulators and originating institutions. We then consider a scenario where banks enter into reinsurance contracting with banks in other regions to mitigate some regional economic risks. These reinsurance contracts may enable banks to improve the performance of their balance sheet assets. Although we find weak correlation among equity returns for regional banks, future high correlation among bank portfolios could pose a problem to regulators because when a bank gets into financial distress this may spill over to other network banks. Widening yield spreads in asset securitizations might serve as an early warning signal of financial distress. Thus, regulators might devote more supervisory resources on originating institutions when their asset securitization yield spreads widen.</span></span></p>

Nontraditional Study Designs for Proving Bioequivalence

From past many years, concerns have been expressed regarding meeting the standard bioequivalence (BE) criteria for highly variable drugs. This has been point of discussion in many conferences and meetings. But to date there is no as such regulatory definition for these drugs or drug products. To pass conventional goal posts for these drugs, the number of subjects required for a study can be much higher than normally needed for a typical BE study. The resources required and the ethical concerns of exposing large number of healthy volunteers to a test drug further poses challenge to the suitability of conventional BE criteria (with an 80-125% acceptance range) for highly variable drugs. Examples exist where a highly variable reference product failed to demonstrate BE when compared to itself in a bioequivalent study using the standard design/sample size.

Perspective: Medical Education Research and the Institutional Review Board: Reexamining the Process

Medical school and residency training curricula across the country have undergone extensive revisions and, much like clinical quality improvement (QI) initiatives, require assessments of new programs. Because sharing knowledge is a hallmark of academic medicine, program evaluation may come under the purview of the institutional review board (IRB); however, the distinction between QI and research is often unclear. And yet a medical education (ME) inquiry can be designed according to either paradigm. The purpose of this article is to bring IRBs and ME researchers closer to a shared understanding of key concepts underlying human participation in research and QI activities, and to consensus on the application of these concepts. The current QI discourse provides a useful framework for making this distinction; the authors identify key theoretical principles and practical considerations derived from this work that are relevant to ME and training, such as the application of the regulatory definition of human subject research to ME inquiries. For ME inquiries defined as human subject research, and therefore subject to IRB review, this article explores the application of the human research regulations to ME research. It concludes with practical suggestions for institutions, IRBs, and ME researchers, which range from formal procedures for making the QI versus research distinction, to instruction in study design and development and the human subject regulatory implications. The intent is to promote a discussion that will result in greater consensus and a more consistent application of the regulatory framework.

Defining public service beyond broadcasting: the legitimacy of different approaches

The development of public broadcasters’ Internet services has compelled practitioners and researchers alike to ponder public service beyond broadcasting. Yet, for public service as a key cultural policy tool, rethinking is also needed on the level of regulatory definitions. Are we witnessing a policy transformation into a media‐neutral public service concept? If so, what are the implications for the legitimacy of public service beyond broadcasting? Relating the current situation to a wider policy context, this article scrutinizes different regulatory approaches, tentatively characterized by (1) extending broadcasting, (2) adding to broadcasting and (3) demoting broadcasting. The approaches are illustrated with three cases: Norway, Germany and the UK. Assessing the different approaches, I discuss advantages and pitfalls, and the implications for the legitimacy of public service freed from broadcasting rationales. As policy actors strive to create stable conditions in an unstable situation, I argue, they should keep in mind both the risks of succumbing to details or pursuing exhaustive lists in basic definitions, and the linguistic and cultural characteristics of each polity.

U.S. FDA requirements for Human Vaccine Product Safety and Potency Testing

The Office of Vaccines Research and Review (OVRR) at the Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA) regulates preventative and therapeutic vaccines for infectious disease indications for use in humans. The framework for regulation of biological products includes Statutes (e.g. The U.S. Food, Drug and Cosmetic Act and the Public Health Service Act), regulations as defined in the Code of Federal Regulations (CFR) and guidance documents. Approval of a biologics license for a product, including vaccines, is based on a demonstration of safety, purity, and potency and assurance that the facility for manufacture, processing, and packaging meets standards to ensure that product released for distribution is safe, pure and potent. The regulatory definitions of safety, purity and potency are detailed in Title 21 of the Code of Federal regulations (CFR) Part 600. All manufacturing information including tests for safety, purity, and potency for a particular product must be documented in the Biologics License Application (BLA). Potency testing may be performed on the final bulk sample or final container sample and may consist of either in vivo or in vitro tests or both. To change a potency or safety test post-licensure requires a Supplement to the License and data to support a modified or alternative test. CBER encourages the development and use of appropriate alternative methods for vaccine safety and potency testing.

Updates on choices of appropriate technology for control of VOC emissions

As the federal, state, and local agencies have promulgated regulations that require greater control for emissions of volatile organic compounds and hazardous air pollutants, new technologies and new strategies for controlling air pollutant emissions have developed. This article updates an earlier article published in Metal Finishing (page 238, vol. 92, no. 5A, 1994) to include some recent developments in air pollutant emission control for solvents used in metal finishing. Volatile organic compounds (VOCs) and Hazardous Air Pollutants (HAPs) have specific regulatory definitions; but for the purpose of this article, organic compounds that are subject to regulatory control as either VOCs or HAPs will be called VOCs, since they are subject to the same types of emission control. VOCs are used in the metal-finishing and other U.S. industries in production, manufacture, and surface coating. With stricter air pollution regulations being promulgated, it is necessary for industry to minimize its use of solvents and/or control solvent emissions. In some cases it may be possible to substitute other compounds; in other cases control technologies will be required to minimize emissions of the regulated compounds. A number of control technology choices are available to control the emissions of VOCs. Two possible approaches to control VOC emissions are recovery and destruction (see Table I). Recovery methods include adsorption and condensation. Destruction methods include incineration and biodegradation. It is also possible to use hybrid combinations such as concentration with condensation or concentration with oxidation. The choice of control technology will depend on economic, safety, and/or regulatory factors. Recovery technologies provide the benefit of both cost and energy savings. Recovery saves the energy for production of new material and the cost of purchasing additional material for the same or a similar application. Destruction technologies provide the benefit of not requiring subsequent disposal of the VOC. High-value VOCs favor recovery methods. Mixtures of VOCs or low-value solvents favor destruction methods.

Thrombocytopenia after vaccination: Case reports to the US Vaccine Adverse Event Reporting System, 1990–2008

We reviewed thrombocytopenia (TP) reports to the US Vaccine Adverse Event Reporting System (VAERS). We examined TP patterns for differences in single versus multiple immunization reports, presence of a live viral vaccine, seriousness, age, and interval to symptom onset. We found 1510 reports of possible TP and after exclusions evaluated 1440 for possible causes. Most (1078; 75%) met the regulatory definition of a serious adverse event. TP was reported after inactivated and live viral vaccines. Platelet counts <10×109/L were reported. Identified vaccines could be prioritized for hypothesis-testing studies.

Risk of Kava Hepatotoxicity and the FDA Consumer Advisory

IN EARLY 2002, THE US FOOD AND DRUG ADMINISTRAtion (FDA) began advising consumers of the potential risk of severe liver injury associated with the use of kava-containing dietary supplements. Kava (Piper methysticum) is a plant indigenous to the South Pacific Islands, where it is commonly used to prepare a traditional beverage for social and recreational purposes. Dietary supplements containing the herbal ingredient kava are promoted for relaxation to relieve stress, anxiety, and tension, as well as for sleeplessness and menopausal symptoms. Kava-containing products have been associated with rare liver injuries in Western countries, and the FDA urged consumers and health care professionals to report any case of liver injury that may be related to the use of kava-containing dietary supplements. The FDA also announced its intention to further investigate the relationship, if any, between the use of dietary supplements containing kava and liver injury, which included attempting to determine a biological explanation for the relationship and to identify the different sources of kava in the United States and Europe. Subsequent analyses by the World Health Organization have shown that the use of kava was associated with the development of liver disease in rare cases, confirmed by structured, quantitative, and liver-specific causality assessment methods. There is now sound evidence that liver injury was caused by both the traditional water-based kava extracts of the South Pacific and the medicinal solvent-based kava extracts of Western countries, with flavokavain B as one of the possible culprits. It remained unclear, however, to what extent the use of ethanol or acetone as solvents might have increased the hepatotoxic risks in patients who consumed medicinal kava extracts. Further assessments of the pathogenetic factors of kava hepatotoxicity revealed the use of inappropriate kava varieties and plant parts. Previously, the existence of more than 200 kava varieties, also called cultivars, had not been considered from the aspects of safety concerns and pharmacovigilance issues. Consequently, in Western countries as well as in the South Pacific region, there has been no regulatory definition advising which of the various kava cultivars should preferentially be used for kava beverages, drugs, and dietary supplements. Specific issues also emerged regarding the peeled kava rhizome that should have been used, but evidence suggests also the use of the kava plant’s aerial parts, which may contain the hepatotoxic alkaloid pipermethysticin. Considering the poor quality of kava raw material used for this small number of kava products, liver injury by kava is basically a preventable disease. Legal steps to improve safety of kava products had already been initiated at about the same time as the FDA consumer advisory was issued. The Vanuatu Kava Act No. 7 of 2002 describes some protection rules of kava for export, which include kava drugs and kava dietary supplements. The Vanuatu legislation differentiates 4 groups of kava cultivars with the noble cultivars as the only group with the option for export. The legislation explicitly excludes other groups of kava cultivars, such as medicinal cultivars and 2-day cultivars, which have previously been used for kava drugs. Excluded from export are plant parts such as stumps, shoots, growing buds, and lateral branches. Kava or kava products may only be exported when each of the following is clearly marked: name of the variety, island of origin, distinct organs of the kava, and the words “Original Vanuatu Kava.” Kava quality requirements for export purposes include a minimum maturation time for the kava plant at harvest of 5 years. It appears that legislation-enforced quality standards for kava products are a first step for increasing their safety in human use. The group of exportable kava varieties consists of 28 noble kava cultivars, but the Vanuatu legislation provides no preference for one single cultivar. In Vanuatu, the major kava producer and exporter, the traditional kava beverage is prepared by cold water extraction of its roots. Historic use shows that kava is safe under the strict control of the rituals of Pacific cultures. The traditional beverage is consumed on a daily basis without apparent adverse effects, and kava cultivars considered as noble ones have a long tradition of safe use.

The quality of commercially available nutraceutical supplements and food sources

Nutraceuticals are components of dietary origin, with claimed beneficial therapeutic activities. The quality of nutraceuticals is paramount for efficacy and safety, and it includes quality of raw materials, different available chemical forms, complex products, lack of substitution of inappropriate materials, and the absence of contaminants. The aim of this review is to investigate the extent of substandard formulated and raw material nutraceuticals, and to highlight any consequent health concern. Reports of the quality of raw materials have revealed wide variations, often as a result of lack of clear regulatory definitions with respect to size of polymeric entities and also presence of glycosidic and salt forms. Published evaluations of over 70 formulations of 25 different nutraceuticals revealed variable quality; no nutraceutical showed consistent high quality, but a number revealed consistent low quality, thereby making the case for closer regulation of manufacturers. Whole food sources have also been shown to be widely variable in constituent levels. The effect of different formulations requires consideration, as the different types have been shown to have marked effects on bioavailability. The poor quality of commercially available nutraceuticals has been highlighted. In addition, incidences of side effects and drug interactions are increasing, as consumption of nutraceuticals rises. Pharmacists and health practitioners need to be aware of the scientific literature to advise accordingly.

Is it research?

A hospital's stroke care team believes that for patients with acute cerebral ischemia, a CT angiogram with a perfusion study, rather than simply a routine CT scan, will better direct clinical care. The team will collect data prospectively in a database to document the effect of this new practice. A hospital implements a new program and collects process and outcome data to monitor and improve performance on stroke-related care, including timely receipt of thrombolytic therapy, dysphagia screens for all patients, and deep venous thrombosisprophylaxis for at-risk patients. Are these activities research? This is an increasingly common question, arising most frequently in 2 contexts. In quality improvement (QI) circles, there is considerable concern that the current regulatory definition of research used by institutional review boards (IRBs) may be too sensitive, creating unnecessary burdens on important QI activities.1 In the surgical or procedural setting, in which the history of improvements has followed the path of “surgical innovations” rather than systematic research, there is increasing discussion about the appropriate level of oversight of such activities.2,3 Given the increasing emphasis on evidence-based medicine and the public pressure to improve the quality of health care, the question “Is it research?” will become even more common. The current US regulations define research as a “systematic investigation … designed to develop or contribute to generalizable knowledge” (45CFR46.102d). Since a well-organized QI project involves a systematic change and measurement (of the process or outcome), the question becomes whether it is also “designed” or intended to contribute to generalizable knowledge. The Office of Human Research Protections (OHRP) guidance document (which does not have …

Pharmacokinetics and bioequivalence evaluation of two different atorvastatin calcium 10-mg tablets: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy fasted Chinese adult males

Background: Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor indicated for the prevention of cardiovascular disease and for the treatment of dyslipidemia. Information on the pharmacokinetics of atorvastatin in a Chinese population is lacking, and regulatory requirements necessitate a bioequivalence study for the marketing of a generic product in China. Objective: The aim of the present study was to assess the pharmacokinetics and bioequivalence of a test and branded reference formulation of atorvastatin calcium 10-mg tablets in healthy fasted Chinese male volunteers. Methods: This was a single-dose, randomized-sequence, open-label, 2-period crossover study with a 2-week washout period between doses. Healthy Chinese males were randomly assigned to receive 20 mg of either the test or reference formulation, and 13 blood samples were obtained over a 48-hour interval. Plasma concentrations of parent atorvastatin and ortho-hydroxy-atorvastatin (primary active metabolite) were simultaneously determined using a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters, including C max, T max, t ½, AUC 0−t, and AUC 0−∞), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the logtransformed ratios of AUC and C max of atorvastatin were within the predetermined bioequivalence range (0.80–1.25 for AUC and 0.70–1.43 for C max) as established by the State Food and Drug Administration of China. Tolerability was evaluated throughout the study by vital signs monitoring, physical examinations, 12-lead ECGs, and subject interviews on adverse events (AEs). Results: A total of 66 subjects were assessed for inclusion; 20 were excluded prior to study initiation. Of the 46 healthy subjects (mean [SD] age, 24.1 [2.5] years; height, 170.8 [5.1] cm; weight, 64.6 [6.4] kg; body mass index (BMI), 22.1 [1.7] kg/m 2) who completed the study, 45 subjects (mean [SD] age, 24.1 [2.5] years; height, 171.1 [4.9] cm; weight, 64.8 [6.3] kg; BMI, 22.1 [1.7] kg/m 2) were included in the pharmacokinetic and bioequivalence analyses; 1 subject was excluded from these analyses because he mistakenly received the same formulation in both periods. No period or sequence effect was observed. The mean values of C max, AUC 0−t, and AUC 0−∞) for the test and reference formulations of atorvastatin (8.78 and 10.76 ng/mL, 38.22 and 40.02 ng/mL/h, 42.73 and 44.51 ng/mL/h, respectively) and ortho-hydroxy-atorvastatin (5.78 and 5.77 ng/mL, 47.32 and 48.47 ng/mL/h, 52.36 and 53.14 ng/mL/h) were not significantly different. The 90% CIs for natural log-transformed ratios of C max, AUC 0−t, and AUC 0−∞) of both atorvastatin (0.73–0.91, 0.92–1.02, and 0.91–1.01, respectively) and ortho-hydroxy-atorvastatin (0.83–1.05, 0.92–1.02, and 0.93–1.02) were within the bioequivalence acceptance limits. Three subjects (6.5%) reported a total of 4 mild AEs (1 abdominal discomfort and 3 venipuncture syncope), which were not considered to be associated with administration of the study drug. Conclusions: This single-dose (20 mg) study found that the test and reference formulations of atorvastatin calcium 10-mg tablet met the regulatory definition for assuming bioequivalence in these healthy fasted Chinese male volunteers. Both formulations were generally well tolerated in the population studied. Chinese National Registry Code: 2007L02512.

Bioequivalence evaluation of single doses of two tramadol formulations: A randomized, open-label, two-period: Crossover study in healthy brazilian volunteers

Background: Tramadol is a well tolerated and effective analgesic used to treat moderate to severe pain. Several generic formulations of tramadol are available in Brazil; however, published information regarding their bioequivalence in the Brazilian population is not available. A study was designed for Brazilian regulatory authorities to allow marketing of a generic formulation. Objective: The purpose of this study was to compare the bioequivalence of 2 commercial tablet preparations containing tramadol 100 mg marketed for use in Brazil. Methods: A randomized, open-label, 2 × 2 crossover study was performed in healthy Brazilian volunteers under fasting conditions with a washout period of 12 days. Two tablet formulations of tramadol 100 mg (test and reference formulations) were administered as a single oral dose, and blood samples were collected over 24 hours. Tramadol plasma concentrations were quantified using a validated HPLC method. A plasma concentration-time profile was generated for each volunteer and then mean values were determined, from which C max, T max, AUC 0−∞ k e, and t 1/2 were calculated using a noncompartmental model. Bioequivalence between the products was determined by calculating 90% CIs for the ratios of C max AUC 0−t and AUC0 −∞, values for the test and reference products using log-transformed data. Tolerability was assessed by monitoring vital signs (temperature, blood pressure, heart rate), laboratory tests (hematology, blood biochemistry, hepatic function, urinalysis), and interviews with the volunteers before medication administration and every 2 hours during the study. Results: Twenty-six healthy volunteers (13 men, 13 women) were enrolled in and completed the study. Mean (SD) age was 30 (6.8) years (range, 21–44 years), mean weight was 64 (8.3) kg (range, 53–79 kg), and mean height was 166 (6.4) cm (range, 155–178 cm). The 90% CIs for the ratios of Cmax (1.01–1.17), AUC 0−t (1.00–1.13), and AUC 0−∞. (1.00–1.14) values for the test and reference products fell within the interval of 0.80 to 1.25 proposed by most regulatory agencies, including the Brazilian regulatory body. No clinically important adverse effects were reported; only mild somnolence was reported by 4 volunteers and mild headaches by 5 volunteers, and there was no need to use medication to treat these symptoms. Conclusion: Pharmacokinetic analysis in these healthy Brazilian volunteers suggested that the test and reference formulations of tramadol 100-mg tablets met the regulatory requirements to assume bioequivalence based on the Brazilian regulatory definition.

Mycophenolate mofetil 500-mg tablet under fasting conditions: Single-dose, randomized-sequence, open-label, four-way replicate crossover, bioequivalence study in healthy subjects

Background: Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an immunosuppressive agent indicated for the prophylaxis of organ rejection in allogeneic kidney, heart, or liver transplant recipients. The European regulatory authorities require bioequivalence studies for the marketing of generic products. Objective: The aim of this study was to assess the bioequivalence of a generic (test) and branded (reference) formulation of MMF 500 mg and MPA. Methods: This single-center, single-dose, randomized, open-label, 4-way crossover study was conducted at Anapharm's Clinical Research Facility, Québec, Québec, Canada. Healthy volunteers aged 18 to 55 years were eligible. Subjects were assigned to receive, in randomized order, a single dose of the test and reference formulations of MMF 500 mg under fasting conditions. Because the study design was 4-way replicate, there were 2 test periods and 2 reference periods. The 4 study periods were each separated by a 14-day washout period. Blood samples were collected over a period of 12 hours after administration for the determination of MMF pharmacokinetic properties, and over 48 (±0.5) hours, for MPA properties. Concentrations of the analytes were determined by reverse LC and detected using LC-MS/MS. Pharmacokinetic parameters were calculated from MMF and MPA concentration data using noncompartmental analysis. C max and AUC 0–t were the primary evaluation criteria, while AUC 0∓∞ was a secondary parameter. The drugs were to be considered bioequivalent if the 90% CIs for the test/reference ratios of natural logarithm-transformed values of these parameters (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored using physical examination, including vital sign measurements, laboratory analysis, and adverse-events (AE) monitoring (including patient interview). Results: A total of 103 subjects were enrolled (64 men, 39 women; 101 white, 2 black; mean [SD] age, 38 [10] years; weight, 68.2 [9.1] kg). The 90% CIs were as follows: MMF, C max, 85.94% to 106.63%; AUC 0–t, 91.94% to 102.20%; and AUC 0∓∞, 93.15% to 105.48%; MPA, Cmax, 92.03% to 105.82%; AUC 0–t, 97.42% to 100.59%; and AUC 0∓∞, 96.96% to 100.90%. These values met with the regulatory definition of bioequivalence. A total of 148 AEs were reported (68 in subjects who received the test treatment and 80 in subjects who received the reference treatment). The most commonly reported AEs were procedural pain (13/102 [12.7%] and 10/101 [9.9%] with the test and reference formulations, respectively), procedural site reaction (12 [11.8%] and 4 [4.0%]), and somnolence (7 [6.9%] and 14 [13.9%]). Conclusions: The generic and branded formulations of MMF 500 mg met the European regulatory criteria for assuming bioequivalence, based on the rate and extent of absorption of a single dose under fasting conditions. Both formulations were well tolerated in these healthy volunteers.

A New Soft Law Approach to Nanotechnology Oversight: A Voluntary Product Certification Scheme

I. INTRODUCTION II. THE FUTILE (NEAR TERM) QUEST FOR COMMAND--AND--CONTROL REGULATION A. Demand for Regulation B. Obstacles to Regulation III. THE LIMITS OF CURRENT SOFT LAW APPROACHES IV. A VOLUNTARY SAFETY TESTING CERTIFICATION SCHEME A. Background on Certification Programs B. The Role of Trust in Certification Programs 1. Dispositional and Situational Trust 2. Reputational Trust 3. Institutional or System Trust 4. Associational Trust 5. Trust and Certification Marks: Examples and Implications V. DESIGNING AND IMPLEMENTING A NANOTECHNOLOGY CERTIFICATION PROGRAM A. Requirements of a Nano Safety Testing Certification Program 1. Disclosure and Reporting 2. Premarket Toxicity Testing 3. Risk Management Practices 4. Post-market Surveillance B. Implementation of the Certification Program C. Limitations and Challenges of the Certification Program VI. CONCLUSION I. INTRODUCTION Regulatory oversight of is necessary yet problematic. The necessity of regulation is driven by two related concerns. First, some nanotechnologies, if left unregulated, are likely to pose very real, if currently unknowable, risks of significant health or environmental damage. (1) Second, public confidence in new technologies and in the regulatory agencies that govern them may be permanently damaged if injurious nanomaterials are released without adequate, or at least the perception of adequate, oversight. (2) Despite these considerations, regulation remains problematic. Most regulatory hurdles are currently insurmountable because we still not know exactly what nanotechnology means or encompasses, much less what concrete risks it may pose. Nanotechnology is a poorly defined, insufficiently understood set of diverse products, processes, and technologies that is not easily captured by any existing regulatory definition, model or system. This situation creates a problem for traditional regulatory tools. Government command-and-control regulations require, among many other things, clear definitions of what is to be regulated, understandable compliance requirements, and strong policy-based rationales to justify the regulation. (3) The impropriety, if not questionable legality, of employing traditional regulatory approaches, coupled with growing calls to do something, (4) has created an opportunity for new models of governance and oversight to emerge. (5) Of late, we have seen numerous short term proposals for (6) solutions and the implementation of some soft law mechanisms. None are based on the traditional command-and-control approach, under which government agencies enact detailed regulatory requirements enforced by the threat of penalty. Instead, all reflect a variety of voluntary, cooperative or partnership approaches. (7) However, although these approaches have many advantages, none of the currently operational regimes has fully achieved two obvious and oft-cited goals of regulation: (1) broad industry participation, with sufficient data submission to aid regulators in risk assessments; and (2) reassurance of public stakeholders as to government's role in regulating emerging technologies. (8) Therefore, this Article proposes another soft law option that may better achieve these goals. We propose a voluntary certification scheme under which companies that produce products may obtain a government-supervised certification for specific products if the firms subject those products to specified safety testing, data disclosure and risk management measures. Given differing national regulatory approaches, our proposal is designed primarily for the United States. However, there is nothing in the proposal that could not be adapted for use in other jurisdictions or prevent the creation of an equivalent international scheme. …

Bioavailability of Two Oral Tablet Formulations of citalopram 20 mg: Single-Dose, Open-Label, Randomized, Two-Period Crossover Comparison in Healthy Mexican Adult Subjects

The aim of this study was to compare the bioavailab ility and determine the bioequivalence of one test formul ation (citalopram 20 mg oral tablet) with its correspondi ng list reference-drug formulation in Mexico. A single dose, randomized, open-label, 2-period cro ss- over, post-marketing study with a 2-weeks washout p e- riod between doses was conducted. Blood samples wer e drawn at baseline, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6. 0, 7.0, 8.0, 10.0, 12.0, 24.0, 48.0, 72.0, 96.0 y 120.0 hours af ter dos- ing. Citalopram plasma levels were determined using HPLC assay method. A total of 24 subjects were enrolled in the study. The bioequivalence test drug values were C max of 26.37 ng/ mL, t max of 3.76 h, AUC 0-t of 613.84 h.ng/mL, AUC 0- ∞ of 879.65 h. ng/mL, and reference drug values of C max of 25.50 ng/mL, t max of 3.96 h AUC 0-t of 596.65 h. ng/mL, AUC 0- ∞ of 982.38 h. ng/mL. No period or sequence effect w as observed. In this study in healthy Mexican adult subjects, a single dose of citalopram 20 mg of the test formulation wa s found to be bioequivalent to the corresponding reference formu- lation according to the regulatory definition of bioequivalence based on the rate and extent of abso rp- tion. Both formulations were generally well tolerat ed.

Bioequivalence and pharmacokinetic comparison of two mycophenolate mofetil formulations in healthy Chinese male volunteers: An open-label, randomized-sequence, single-dose, two-way crossover study

Background: Mycophenolate mofetil (MMF) is an ester prodrug of mycophenolic acid (MPA), so clinical studies measure the circulating plasma MPA concentration instead of MMF. MPA is extensively glucuronidated by several uridine diphosphate glycosyltransferases into an inactive 7-O-glucuronide and a pharmacologically active acylglucuronide. Considering the effect of racial differences and genetic factors on the pharmacokinetic (PK) properties of drugs, it is necessary to study them in Chinese populations. Objectives: The aim of this study was to compare the clinical bioequivalence and PK properties of a test (dispersible tablets) and reference (capsules) formulation of MMF 1.0 g in healthy Chinese volunteers. We also established a validated HPLC method for the determination and quantification of MPA in human plasma. The study was required to obtain Chinese regulatory approval for the test formulation. Methods: This open-label, randomized-sequence, single-dose, 2-way crossover study was conducted at the First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 1.0-g dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The plasma concentration of MPA, which is the active metabolite of MMF, was determined using a validated HPLC method. For analysis of PK properties, blood samples were collected at 0, 10, 20, 30, and 45 minutes, and 1, 1.5, 3, 5, 8, 11, 18, 36, and 48 hour(s). The PK parameters, including C max, T max, t ½, AUC 0–48, and AUC 0–∞, were determined from the plasma concentrations of the 2 formulations by noncompartmental analysis. Tolerability was assessed at baseline (be- fore administration) and at 30 minutes and 1, 5, 18, and 48 hours after administration by monitoring vital signs. Laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) were performed for the identification of adverse events (AEs) (eg, leukopenia, thrombocytopenia, anemia). Patient interviews were conducted to assess the occurrence of AEs such as diarrhea, abdominal pain, nausea, vomiting, and secondary infections. The formulations were considered to meet the regulatory requirements of bioequivalence if the log-transformed ratios of C max and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Results: Eighteen healthy Chinese male volunteers (mean [range] age, 23.5 [22–30] years; weight, 63.3 [56–68] kg; height, 171 [165–184] cm) were enrolled and completed the study. The main PK parameters of the MMF test and reference formulations were as follows: mean (SD) T max, 0.68 (0.21) and 0.81 (0.18) hour, respectively; C max, 25.58 (4.79) and 26.47 (3.67) mg/L; AUC 0–48, 59.19 (9.23) and 58.32 (9.28) mg/L/h; t ½, 15.12 (3.17) and 16.04 (4.22) hours; AUC 0–∞), 63.28 (10.23) and 62.41 (10.28) mg/L/h. The mean (SD) relative bioavailability was 101.5% (10.3%). No statistically significant differences were found based on ANOVA. The ratios of C max (0.97) and AUC (1.01) for the test and reference formulations were within the FDA bioequivalence definition intervals of 80% to 125%. No AEs were reported by subjects or found on analysis of vital signs or laboratory tests. Conclusions: In this study in healthy Chinese male volunteers, results from the PK analysis suggested that a single dose of the test and reference formulations of MMF 1.0 g met the regulatory requirements of bioequivalence, based on the FDA regulatory definition (rate and extent of absorption). Both formulations were well tolerated.

Results of a single-center, single-dose, randomized-sequence, open-label, two-way crossover bioequivalence study of two formulations of valsartan 160-mg tablets in healthy volunteers under fasting conditions

Background: Valsartan is a nonpeptide, orally active angiotensin II type 1 receptor blocker used to treat hypertension alone or in combination with other antihypertensive agents. Objective: The aim of this study was to compare the relative bioavailability of a new valsartan 160-mg formulation (ie, test drug) and that of a reference formulation so that bioequivalence could be assessed, as required by European regulatory authorities for the marketing of a generic product. Methods: This was a single-center, single-dose, randomized-sequence, open-label, 2-way crossover study with a minimum washout period of 7 days; drug was administered to healthy volunteers under fasting conditions. Blood samples were collected up to 36 hours postadministration, and valsartan levels were gauged from plasma by reverse liquid chromatography and tandem mass spectrometry detection (ie, the LC-MS/MS method). Pharmacokinetic parameters were calculated from valsartan concentration data using noncompartmental analysis. AUC last, AUC ∞, and C max were analyzed. The 90% CIs of the ratios of the testversus-reference pharmacokinetic parameters (AUC last, AUC ∞, and C max) were obtained by ANOVA on Intransformed data. The 90% CIs were required to be within 80.00% to 125.00% of the 90% CI to meet the criteria for bioequivalence. Tolerability was monitored using physical examination (including vital-sign measurements) and ECG performed at screening, as well as laboratory analysis, including biochemistry tests, hematology tests, and urinalysis, which were performed at screening and during the study period. Results: Thirty-eight white (90.5%), 2 black (4.8%), and 2 Hispanic subjects (4.8%) enrolled in the study; the sample included a total of 27 men and 15 women. The mean (SD) age was 37 (11) years and mean weight was 65.4 (7.6) kg. The 90% CI values for pharmacokinetic measurements were as follows: AUC last, 94.45% to 118.59%; AUC ∞, 93.58% to 116.51%; and C max, 93.61% to 122.02%. Thus, they were all within the predefined 80.00% to 125.00% range. Thirty-six postadministration adverse events were reported; the most common was blood pressure decrease. A decrease of blood pressure was experienced by 6 subjects (14.6%) after the administration of the test formulation, and by 5 subjects (12.5%) after the administration of the reference formulation. Thirtythree of these adverse events were graded as mild and 3 as moderate; 11 were judged as probably related, 12 as possibly related, 3 as remotely related, and 10 as unrelated to the study medication. Conclusions: In this open-label study of healthy volunteers, the test and reference formulations of valsartan 160 mg met the European regulatory definition of bioequivalence, based on the rate and extent of absorption of a single dose under fasting conditions. Both formulations were well tolerated.

Bioequivalence of two formulations of glucosamine sulfate 500-mg capsules in healthy male chinese volunteers: An open-label, randomized-sequence, single-dose, fasting, two-way crossover study

Background: Glucosamine sulfate is used for the treatment of arthrosis, especially osteoarthritis of the knee joint. The available evidence suggests differences in its pharmacokinetics in Chinese subjects compared with non-Chinese subjects. Objective: The aim of this study was to compare the pharmacokinetics and relative bioavailability of a test and reference formulation of glucosamine sulfate 500 mg after single oral administration in healthy Chinese volunteers. Methods: This open-label, randomized-sequence, single-dose, 2-way crossover study was performed at the First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 500-mg dose of the test or reference capsule formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Glucosamine sulfate was assayed using a liquid-chromatography tandem mass spectrometry method. For analysis of pharmacokinetic properties, including C max, AUC 0−t, and AUC 0−∞), blood samples were obtained at intervals over a 14-hour period after study drug administration. The formulations were considered bioequivalent if the log-transformed ratios of C max and AUC were within the predetermined equivalence range (70%–143% for C max and 80%–125% for AUC) as established by the State Food and Drug Administration (SFDA) of China. Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis), and by questioning subjects about adverse events (AEs). Results: Twenty–two healthy male Chinese subjects were enrolled (mean [range] age, 24 [22–26] years; weight, 63.9 [58.5–69.3] kg; height, 172 [167–177] cm); all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of C max, AUC 0−t, and AUC 0−∞) were 93.4 to 127.3, 92.4 to 114.5, and 92.7 to 114.6, respectively (all, P = NS). The AUC 0−∞ of the test and reference formulations was 1.83 (0.66) and 1.77 ( 0.72) μg/h/mL, respectively. No AEs were observed or reported during the study. Conclusions: In this small study in healthy male Chinese volunteers, a single 500-mg dose of the test formulation met the SFDA's regulatory definition for bioequivalence to the reference formulation. Both formulations were well tolerated.