Development of aquatic life criteria for selenium: a regulatory perspective on critical issues and research needs

The US is currently in the process of revising its freshwater, chronic aquatic life criterion for selenium. The fundamental issues being addressed include which environmental compartment(s) support the most reliable expression of the criterion, which form(s) of selenium should be measured in the medium (media) of choice, and which site-specific water quality (or other factors) should be linked to the expression of the criterion. Literature reviews and a recent workshop were conducted to assess the state of the science on various issues related to water-, tissue- and sediment-based criteria for selenium. Evaluation of many of these issues is ongoing. In terms of water column criteria issues, data limitations will likely restrict the expression of a criterion to operationally defined forms (e.g. total recoverable, dissolved). The specific identity of organoselenium in natural systems is lacking and may not be appropriately represented by free seleno-amino acids (e.g. selenomethionine). The available data do not appear to support quantitative relationships between chronic toxicity and water quality characteristics. In terms of a tissue-based criterion, reproductive tissue (ovary, egg) has been recommended as the tissue of choice, but practical concerns and data availability require consideration of other tissues (e.g. whole-body). Organoselenium (bound to peptides or proteins) is thought to be the form of greatest toxicological importance in fish, however, direct measurements of organoselenium compounds in tissues are very limited. Route of exposure (food vs. water uptake) may prove important for establishing diagnostic tissue residues for selenium based on laboratory data. Data on toxicological aspects of selenium in sediments appear sparse, particularly in relation to different sedimentary forms. Reliable assessments of bioaccumulation will likely be critical for making site-specific modifications to chronic selenium criteria, however, many technical issues for assessing bioaccumulation remain. The need for improved analytical methods for directly speciating organoselenium in various environmental media underpins many of the current data gaps. Improving analytical methodologies to enable affordable and reliable measurement of organoselenium compounds holds significant promise for advancing selenium ecotoxicological research.     

Levothyroxine: therapeutic use and regulatory issues related to bioequivalence

Levothyroxine is the overwhelming choice of clinicians for the treatment of hypothyroidism and for the suppression of goitre and thyroid nodules in selected cases. The monitoring of serum levels of thyroid stimulating hormone is necessary for appropriate dosage adjustment of levothyroxine. Levothyroxine has a narrow therapeutic index: both underdosage (subclinical hypothyroidism) and excessive dosage (subclinical hyperthyroidism) are associated with adverse symptoms and pathophysiological effects and are to be avoided. The consequent necessity for careful titration of doses has had an impact on the issue of switchability, or bioequivalence, of the various marketed levothyroxine products. In this article, the basis for concern about currently accepted standards of the FDA for pharmacological bioequivalence are examined in the context of levothyroxine. The history and status of the recent request by the FDA for a new drug application for all levothyroxine products, and its impact on the market leader Synthroid^®, is also discussed.     

Clinical trials in psychopharmacology: scientific and ethical issues.

1. The ethical and scientific use of medicines for the treatment of illness rests upon proof that the medicines to be used are effective and safe for the condition to be treated. The use of the clinical trial is the method by which such evidence is produced. 2. Recent activities by some to decry clinical trials as unethical and restrict their conduct results in the totally unacceptable situation of withholding potentially valuable treatments from patients or subjecting patients to the unnecessary risks of treatments not proven safe and efficacious. These actions can lead to a new dark age of "chemotherapeutic blood letting and purgatives" under the guise of higher ethical purposes.     

Levothyroxine: therapeutic use and regulatory issues related to bioequivalence

Levothyroxine is the overwhelming choice of clinicians for the treatment of hypothyroidism and for the suppression of goitre and thyroid nodules in selected cases. The monitoring of serum levels of thyroid stimulating hormone is necessary for appropriate dosage adjustment of levothyroxine. Levothyroxine has a narrow therapeutic index: both underdosage (subclinical hypothyroidism) and excessive dosage (subclinical hyperthyroidism) are associated with adverse symptoms and pathophysiological effects and are to be avoided. The consequent necessity for careful titration of doses has had an impact on the issue of switchability, or bioequivalence, of the various marketed levothyroxine products. In this article, the basis for concern about currently accepted standards of the FDA for pharmacological bioequivalence are examined in the context of levothyroxine. The history and status of the recent request by the FDA for a new drug application for all levothyroxine products, and its impact on the market leader Synthroid, is also discussed.     

Non-inferiority clinical trials: Practical issues and current regulatory perspective

Non-inferiority clinical trials are being performed with an increasing frequency now-a-days, because it helps in finding a new treatment that have approximately the same efficacy, but may offer other benefits such as better safety profile. Non-inferiority clinical trials aim to demonstrate that the test product is no worse than the comparator by more than a pre-specified small amount. There are several fundamental differences between non-inferiority and superiority trials. Some practical issues concerning the non-inferiority trials are assay sensitivity, choice of the non-inferiority margin, sample size estimation, choice of active-control, and analysis of non-inferiority clinical trials. For serious infections such as hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, community-acquired bacterial pneumonia, and acute bacterial skin and skin structure infections, the United States Food and Drug Administration (US FDA) has recently recommended that it is possible to define a reliable and consistent estimate of the efficacy of active treatment relative to placebo from available data, which can serve as the basis for defining a new inferiority margin for an active-controlled, non-inferiority trial. But for some indications with a high rate of resolution without antibacterial drug therapy such as acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and acute bacterial otitis media (ABOM), the US FDA has recommended that the available data will not support the use of a non-inferiority design and other trial designs (i.e., superiority designs) should be used to provide the evidence of effectiveness in these three indications.     

缺血性中风抗氧化治疗的临床问题及研究进展

抗氧化剂可以显著降低氧化应激损伤,对缺血性中风具有神经保护作用.然而,抗氧化剂的有效性及副作用问题极大地限制了其临床发展.研究表明,反应氧族(ROS)不仅是缺血性脑损伤的核心因素,而且参与了病后恢复期的组织修复,抗氧化剂的使用障碍可能与ROS复杂的生理作用有关.本文以优化抗氧化剂的使用为目的,阐述缺血性中风后ROS的多重病理生理作用,并对当今抗氧化治疗药物进行综述,通过分析药物运用存在的问题,拟为抗氧化剂基础研究和临床应用提供新的思路.     

Subgroup analyses in randomized clinical trials: statistical and regulatory issues

Recently, two CPMP Points to Consider, one on adjustment for baseline covariates and the other on multiplicity issues in clinical trials, have included recommendations on the use of subgroup analysis for regulatory purposes. However, despite their regular use and regulatory attention, the validity and nature of subgroup analyses are still frequently questioned. This article provides guidance on when subgroup analyses can be done, when they should be done, and their interpretation. The validity of common regulatory claims based on subgroup analyses is then discussed.     

Analytical difficulties facing today's regulatory laboratories: issues in method validation

The challenges facing analytical laboratories today are not unlike those faced in the past, although both the degree of complexity and the rate of change have increased. Challenges such as development and maintenance of expertise, maintenance and up-dating of equipment, and the introduction of new test methods have always been familiar themes for analytical laboratories, but international guidelines for laboratories involved in the import and export testing of food require management of such changes in a context which includes quality assurance, accreditation, and method validation considerations. Decisions as to when a change in a method requires re-validation of the method or on the design of a validation scheme for a complex multi-residue method require a well-considered strategy, based on a current knowledge of international guidance documents and regulatory requirements, as well the laboratory's quality system requirements. Validation demonstrates that a method is 'fit for purpose', so the requirement for validation should be assessed in terms of the intended use of a method and, in the case of change or modification of a method, whether that change or modification may affect a previously validated performance characteristic. In general, method validation involves method scope, calibration-related parameters, method precision, and recovery. Any method change which may affect method scope or any performance parameters will require re-validation. Some typical situations involving change in methods are discussed and a decision process proposed for selection of appropriate validation measures.     

Good laboratory practices and other regulatory issues: A European view

Safety pharmacology studies provide information on the effects of new chemical entities on physiological function in experimental animals and complement classical toxicology studies which assess effects on bodily structure. Data from these studies help to predict possible adverse effects of a compound that might be seen during administration to man, and should therefore be classified as safety studies. It is a regulatory requirement in most areas of the world that safety studies be carried out in compliance with the principles of Good Laboratory Practice. The way in which United Kingdom pharmaceutical companies approach safety pharmacology has been surveyed, and a comparison has been made with practices in the United States. © 1995 Wiley-Liss, Inc.     

Clinical pharmacy services: Part II--the issues

The development of clinical pharmacy programs over the past decade has been both dramatic and satisfying as well as divisive and frustrating. In our experience the broad spectrum of possible clinical activities is responsible for both situations as it concerns the individual pharmacist. At Sunnybrook, liaison pharmacists have accepted departmentally prioritized clinical activities as their primary focus while removed from the distribution system. Documentation for each individual staff member, satellite and departmental achievements for patient counselling, adverse reaction and drug information programs was undertaken to provide visible endpoints for both staff and administration. Hospital Pharmacy visibility to the lay public, a need expressed by several prominent practitioners, has been addressed by the production of a Pharmacy Services Brochure which helps to educate in-patients about our many programs. Lastly the attempt by several colleagues to evaluate the profession's clinical impact by means of a quality assurance program illustrates the difficult task ahead of us if we are to indeed demonstrate an improved patient care program through our efforts.