Achieving reimbursement for regenerative medicine products in the USA.

Achieving reimbursement for regenerative medicine products is potentially a greater challenge than gaining US FDA approval, making it a decisive factor in the success or failure of small businesses. However, the mechanisms by which reimbursement is achieved are still seen as something of a 'black box', especially to those outside of the USA. This report aims to provide insights into the mechanisms of reimbursement and variety of payers in the USA, and to act as a starting point for a successful US reimbursement strategy. Fundamental concepts such as coverage, payment and coding are explained and linked with the factors that potentially determine the successful reimbursement of regenerative medicine products, including cost of goods and clinical study design. Finally, important considerations for the design of clinical studies that satisfy both the payers and the FDA are discussed and the key elements of a successful company strategy identified.

Automated, serum-free production of CTX0E03: a therapeutic clinical grade human neural stem cell line.

Automation of cell culture processes is necessary to achieve scalable and reproducible manufacture of cell-based therapies. CTX0E03 is a near-clinic neural stem cell line for stroke therapy. The transfer of the CTX0E03 manufacture process from a manual to a completely automated process is demonstrated by (a) adapting the manual process to conform to the automated platform and (b) conducted a large scale (20 x T175 flasks) automated CTX0E03 expansion in accordance with the working bank to drug substance lot manufacture schedule. The automated lot was within the GMP release specification for viability, growth rate, nestin immunoreactivity and transcriptome equivalence.

Results from an exploratory study to identify the factors that contribute to success for UK medical device small- and medium-sized enterprises.

This paper reports the results from an exploratory study that sets out to identify and compare the strategic approaches and patterns of business practice employed by 14 UK small- and medium-sized enterprises to achieve success in the medical device sector of the health-care industry. An interview-based survey was used to construct individual case studies of the medical device technology (MDT) companies. A cross-case analysis was performed to search for patterns and themes that cut across these individual cases. Exploratory results revealed the heterogeneity of MDT companies and the distinctive features of the MDT innovation process that emphasize the importance of a strategic approach for achieving milestones in the product development and exploitation process and for creating value for the company and its stakeholders. Recognizing the heterogeneity of MDT companies, these exploratory findings call for further investigation to understand better the influence of components of the MDT innovation process on the commercialization life cycle and value trajectory. This is required to assist start-up or spin-out MDT companies in the UK and worldwide to navigate the critical transitions that determine access to financial and consumer markets and enhance the potential to build a successful business. This will be important not only for bioscience-based companies but also for engineering-based companies aiming to convert their activities into medical devices and the health- and social-care market.

Application of process quality engineering techniques to improve the understanding of the in vitro processing of stem cells for therapeutic use.

The translation of experimental cell-based therapies to volume produced commercially successful clinical products requires the development of capable, economic, scaleable (and therefore frequently necessarily automated) manufacturing processes. Application of proven quality engineering techniques will be required to interrogate, optimise, and control in vitro cell culture processes to regulatory and clinically acceptable specifications. We have used a Six Sigma inspired quality engineering approach to design and conduct a factorial screening experiment to investigate the expansion process of a population of primary bone marrow-derived human mesenchymal stem cells on a scaleable automated cell culture platform. Key cell culture process inputs (seeding density, serum concentration, media quantity and incubation time) and important cell culture process responses (cell number and the expression of alkaline phosphatase, STRO-1, CD105 and CD71) were identified as experimental variables. The results rank the culture factors and significant culture factor interactions by the magnitude of their effect on each of the process responses. This level of information is not available from conventional single factor cell culture studies but is essential to efficiently identify sources of variation and foci for further process optimisation. Systematic quality engineering approaches such as those described here will be essential for the design of regulated cell therapy manufacturing processes because of their focus on identifying the sources of and the control of variation, an issue that is at the core of current Good Manufacturing Practice.

On the process capability of the solid free-form fabrication: a case study of scaffold moulds for tissue engineering.

This study applies the methodology and procedure of process capability to investigate a solid free-form fabrication technique as a manufacturing method to produce scaffold moulds for tissue engineering. The process capability Cpk and process performance Ppk of scaffold mould manufacture using a solid free-form fabrication technique has been analysed with respect to the dimension deviations. A solid free-form fabrication machine T66 was used to fabricate scaffold moulds in this study and is able to create features that ranged from 200 microm to 1000 microm. The analysis showed that the printing process under the normal cooling conditions of the printing chamber was in statistical control but gave low process capability indices, indicating that the process was 'inadequate' for production of 'dimension-consistent' scaffold moulds. The study demonstrates that, by lowering the temperature of the cooling conditions, the capability Cpk of the printing process can be improved (about threefold) sufficiently to ensure the consistent production of scaffold moulds with dimension characteristics within their specification limits.

Business models and leadership styles in small medical device and bio-science businesses--examples in a region and their implications.

This paper reviews the leadership styles and business models found in small technologically based businesses operating in the healthcare sector within one of the UK regions, the East Midlands. The most frequently encountered business model strands were 1) mixed economies: that fund development with service income; cross-sectoral product portfolios; and decoupled business portfolios led by a single entrepreneur and 2) scale sensitive "stay small" models including the avoidance of venture capital; "early exit"; and virtual business strands. There was found to be little correlation between leadership style and business model for the small number of businesses surveyed. The avoidance of venture capital is in direct contrast to adjacent regions.

Current methods for the measurement of growth hormone in urine.

Since the development of sensitive immunoassay procedures for the measurement of GH in urine, a urinary GH determination has been proposed as an alternative way of assessing pituitary GH secretion. Whilst studies on the clinical application of these assays have been difficult to correlate, for the reasons described, it is clear that an estimation of urinary GH has a useful role in clinical and physiological studies in both children and adults.

Urinary excretion and clearance of insulin in diabetic and normal children and adolescents.

Seventy-two diabetic (38 males) and 86 normal (41 males) children provided timed overnight urine collections. Fourteen of the diabetic and 33 of the normal children had concurrent overnight plasma insulin profiles. Urinary insulin clearance in the diabetic subjects was compared with excretion of albumin, growth hormone, retinol-binding protein, and N-acetyl-beta-D-glucosaminidase. In the normal subjects, urinary insulin excretion correlated with mean overnight plasma levels in the boys (r = 0.82, p < 0.001) but not in the girls (r = 0.32), and varied with puberty stage in the boys. Insulin clearance was greater in boys than girls during puberty, and fell in both sexes with advancing puberty. Insulin excretion was greater in diabetic than normal children in both sexes at all puberty stages. Insulin clearance was also greater in diabetic than normal subjects (1.05 +/- 0.1 ml min-1 1.73 m-2 vs 0.48 +/- 0.05 ml min-1 1.73 m-2, p < 0.001). Insulin excretion as a percentage of the filtered load was also greater in diabetic than normal subjects (1.9 +/- 0.27% vs 0.85 +/- 0.09%, p < 0.01). In the diabetic children, there was a correlation between urinary insulin and growth hormone excretion (r = 0.52, p < 0.02), and retinol-binding protein in those (n = 10) with higher retinol binding protein excretion (r = 0.76, p = 0.01). The value of urinary insulin excretion as a measure of free plasma insulin levels in normal and diabetic children may be limited by sex differences in renal insulin clearance, and by proximal renal tubular dysfunction in children with diabetes.

Urinary growth hormone excretion during puberty in type 1 (insulin-dependent) diabetes mellitus.

The excretion of urinary growth hormone was measured by a highly sensitive direct immunoradiometric assay in a cross-sectional study during puberty in 70 children with Type 1 (insulin-dependent) diabetes mellitus and 94 normal children. In normal children (n = 24) and diabetic children (n = 17) overnight urinary growth hormone excretion correlated significantly with the mean overnight plasma concentration (r = 0.70, p less than 0.001, and r = 0.70, p less than 0.001), indicating that urinary GH excretion reflects the circulating endogenous GH level. Overnight urinary growth hormone excretion increased during puberty. In normal and in diabetic children there was a peak in boys at genital stage 4 (both p less than 0.01), and in girls at breast stage 2 (both p less than 0.02). The diabetic children excreted more urinary growth hormone than the normal children at every pubertal stage. Excretion of albumin, retinol binding protein and N-acetyl-beta-D-glucosaminidase was measured in urine from 38 diabetic children. Urinary growth hormone correlated weakly with urinary albumin (r = 0.49, p less than 0.01), retinol binding protein (r = 0.42, p less than 0.01), and N-acetyl-beta-D-glucosaminidase (r = 0.43, p less than 0.01). Urinary GH excretion was not related to blood glucose control (HbA1) in boys (n = 31) or girls (n = 39). The measurement of urinary growth hormone provides an assessment of endogenous growth hormone during puberty in normal and diabetic children. However, caution must be exercised in interpreting urinary growth hormone data from diabetic patients with increased excretion of albumin and retinol binding protein.

Urinary growth hormone during puberty in normal and diabetic children.

The measurement of GH in urine may have many clinical applications, particularly in childhood. We have used a highly sensitive direct immunoradiometric assay to examine urinary GH excretion in children during puberty. Fifty-five healthy schoolchildren collected timed overnight urine samples. A further 36 children (15 normal, six of short stature and 15 diabetic) collected urine samples during a total of 50 overnight plasma GH secretory profiles (15-min sampling). Overnight urinary GH excretion increased during puberty, with a peak at breast stage 2 in girls, and genital stage 4 in boys, before declining at stage 5. There was a positive correlation (r = 0.57, p = 0.003) with height velocity in girls, but not in boys. At each puberty stage except 2, the diabetics excreted more urinary GH than the normal children. There was a highly significant correlation (r = 0.79, p less than 0.001) between mean overnight plasma GH concentrations and urinary GH excretion, suggesting that the latter accurately reflects physiological GH secretion.

Measurement of human growth hormone in urine: development and validation of a sensitive and specific assay.

A specific solid-phase immunoradiometric assay (IRMA), optimized for maximum sensitivity, has been developed for measurement of human GH (hGH) in urine. The sensitivity varied with sample size, giving a range of 0.001 to 0.003 mU/l for a sample volume of 2 ml. Recovery and dilution experiments, together with chromatography of urine samples, indicate that the method is specific for hGH. Added exogenous hGH was measured with a mean recovery of 101 +/- 10% (S.D.) for 1 ml samples and 87 +/- 8% for 2 ml samples. Measurements of samples diluted at 1:2 and 1:4 gave values of 97.4 and 96.6% respectively of those expected. Cross-reactions of human placental lactogen and prolactin were less than 0.008 and 0.04% respectively on a mol/mol basis. The assay was insensitive to the presence of NaCl (50-500 mmol/l), urea (50-1000 mmol/l), creatinine (1-20 mmol/l), Ca2+ ions (1-20 mmol/l), SO4(2-) ions (1-1000 mmol/l), Mg2+ ions (0.05-50 mmol/l), 0.5-5% (w/v) glucose and a pH range of 6-9. Chromatography of unextracted samples showed that the immunoreactive material in urine eluted in a single homogenous peak with a similar position to monomeric pituitary hGH (22 kDa). Administered hGH (0.002%) was recovered in urine collected over a 2-h period following an intravenous injection. The urine output of hGH showed a good correlation with serum hGH in 18 patients following routine insulin tolerance tests and in 25 patients following an oral glucose tolerance test.(ABSTRACT TRUNCATED AT 250 WORDS)