Diabetes control and complications: the role of glycated haemoglobin, 25 years on.

The long-term complications of diabetes have major consequences for individual subjects and growing healthcare delivery and cost implications for society. Evidence for the benefits of good glycaemic control, as monitored by glycated haemoglobin measurements, has been developed in the 25 years since they were introduced to the point where HbA(1c) assays play central roles in patient management, clinical guidance and audit, and clinical trial design. In this review this evidence is examined and three classes of uncertainty identified that diminish confidence in the effectiveness of these roles for HbA(1c). 1 Analytical variability between different methods for HbA(1c) has restricted the application of clinical targets and this problem has recently been addressed by reference method standardization. There are two approaches to this which result in different HbA(1c) values and this discrepancy needs to be resolved. 2 Biological variability in HbA(1c) values between individuals also restricts its predictive role when applied to populations. The correlations between HbA(1c) measurements and various components of glycaemia (overall, fasting, postprandial) are still uncertain and differences in protein glycation and de-glycation are greater between subjects than often thought. The influence of variability in erythrocyte life span is an area where research is needed, especially in diabetic subjects. 3 Clinical variability is the most important and complex area of uncertainty. A predictive link between HbA(1c) and clinical outcomes is not as clear-cut as often stated. The correlation with the development of microvascular disease is well established in Type 1 diabetes, but in Type 2 subjects (90% of those with diabetes) the evidence that HbA(1c) monitoring is of value in predicting or preventing macrovascular disease is not strong, although it is the major cause of morbidity and early death in this group. It is recommended that, as a matter of urgency, these issues be examined, particularly within the context of self-care in diabetes.

Clinical pathology accreditation: standards for the medical laboratory.

This article describes a new set of revised standards for the medical laboratory, which have been produced by Clinical Pathology Accreditation (UK) Ltd (CPA). The original standards have been in use since 1992 and it was recognised that extensive revision was required. A standards revision group was established by CPA and this group used several international standards as source references, so that the resulting new standards are compatible with the most recent international reference sources. The aim is to make the assessment of medical laboratories as objective as possible in the future. CPA plans to introduce these standards in the UK in 2003 following extensive consultation with professional bodies, piloting in selected laboratories, and training of assessors.

Rapid responses of British butterflies to opposing forces of climate and habitat change.

Habitat degradation and climate change are thought to be altering the distributions and abundances of animals and plants throughout the world, but their combined impacts have not been assessed for any species assemblage. Here we evaluated changes in the distribution sizes and abundances of 46 species of butterflies that approach their northern climatic range margins in Britain-where changes in climate and habitat are opposing forces. These insects might be expected to have responded positively to climate warming over the past 30 years, yet three-quarters of them declined: negative responses to habitat loss have outweighed positive responses to climate warming. Half of the species that were mobile and habitat generalists increased their distribution sites over this period (consistent with a climate explanation), whereas the other generalists and 89% of the habitat specialists declined in distribution size (consistent with habitat limitation). Changes in population abundances closely matched changes in distributions. The dual forces of habitat modification and climate change are likely to cause specialists to decline, leaving biological communities with reduced numbers of species and dominated by mobile and widespread habitat generalists.

The role of bioassays in the development, licensing and batch control of biotherapeutics.

The role of bioassays in ensuring the safety and efficacy of medicines produced by biotechnology intended for human use is under continuous review. It is a complex area, in which the rapid scientific and technological advances have been accompanied, more or less synchronously, by novel clinical applications. The need to match the rapidity of these developments with the necessarily more cautious regulatory procedures for licensing and controlling medicines in the pharmaceutical marketplace has produced an area of active debate. This article reviews the debate and its practical consequences, while maintaining the pre-eminence of the underlying scientific values.

The First International Standard for Somatropin: report of an international collaborative study.

Following an earlier decision to move away from the in vivo bioassay for determination of the potency of therapeutic somatropin (recombinant DNA human growth hormone), 18 laboratories in 12 countries participated in an international collaborative study designed to establish an international standard for somatropin, calibrated both by bioassay and by physicochemical assays of somatropin content. The mean in vivo biological potency of preparation studied, coded 88/624, was 6.75 IU/ampoule (fiducial limits 6.30-7.23). Determination of the protein content by quantitative amino-acid analysis yielded a mean estimate of 1.98 mg protein per ampoule. (Relative standard deviation = 2.88%). Data from the study also yielded mean values of 97.2% +/- 0.8% for the monomer content of the preparation, and 8.18 (RSD = 4.00%) for A1% at 276 nm. At its 45th meeting, in October 1994, the ECBS of WHO formally established the preparation 88/624 as the First International Standard for Somatropin, with a defined content of 2.0 mg protein per ampoule, and a defined specific activity of 3.0 International Units per milligram.

The role of bioassays in the assessment of recombinant proteins.

Although the need is diminishing, biological assays still have an important place in the characterization and quality control of therapeutic peptides prepared by recombinant DNA technology. This role needs to be assessed on a case-by-case, product-by-product basis. It includes as a minimum the need to establish during product development the range and quantitative nature of its biological activities, particularly those relevant to its intended clinical use and potential side effects. For those products whose quality and consistency can be established by alternative approaches, then a biological assay may no longer be necessary on a batch basis. For others, bioassays will be required until adequate and appropriate alternatives can be shown, through international collaborative studies, to be sufficient to assure the product's efficacy and safety in clinical use. So-called "bio-identity" tests are inappropriate and should not be used.

Analysis of therapeutic growth hormone preparations: report of an interlaboratory collaborative study on growth hormone assay methodologies.

Recombinant DNA-derived human growth hormone (somatotropin) is widely used to treat growth hormone-deficient children. The potency of this product is determined by in-vivo bioassay in hypophysectomized rats, which is imprecise, costly and invasive, and there have been suggestions that it could safely be replaced with in-vitro or physico-chemical alternatives. In this report we present the results of a collaborative study designed to test this proposal. Somatotropin was modified by mild or severe proteolysis, mild or severe oxidation or treatment at high pH, and compared in a multi-centre collaborative study with unmodified somatotropin or with dimerized somatotropin. Participating laboratories included manufacturers and national control laboratories, and pharmacopoeial bioassays were compared with in-house in-vitro and physico-chemical bioassays. Although performing adequately with untreated somatotropin, for degraded samples the in-vivo bioassays were relatively unresponsive to changes in the growth hormone molecule. In contrast, the physico-chemical assays, in particular the reverse-phase HPLC, performed with a high degree of selectivity. We conclude that in the case of somatotropin, the in-vivo bioassay can be removed from the routine product specification with an acceptable degree of security. This however does not obviate the requirement rigorously to demonstrate biological activity in-vivo during product development, nor may the conclusions of this study be applied to other therapeutic recombinant proteins without similar collaborative investigations.