Molecular "Sameness" Is the Key Guiding Principle for Extrapolation to Multiple Indications.

Much has been made of biosimilars as a new regulatory concept, yet it is clear that misunderstandings are widespread, including the scientific justification for use in all indications of the reference product or "extrapolation." However, as this article shows, biosimilarity and extrapolation are not new concepts and most patients being treated with a branded biologic have already received a similar version of the original reference biologic based on changes in the manufacturing process.

Toward interchangeable biologics.

A biosimilar is designed to match the reference product--to be as close to the reference as the reference is to itself considering batch-to-batch variability and manufacturing changes over its lifetime. Interchangeability will require additional data, however, the interchangeable biologic itself will be the same as that approved for biosimilarity.

The continuum of comparability extends to biosimilarity: how much is enough and what clinical data are necessary?

Experts debate the clinical evidence standards needed to approve major manufacturing changes for biologics, biosimilars, and interchangeable biosimilars. As sponsors consider their development plans, the resource investment required to develop an analytically highly similar candidate must be balanced by regulatory relief for the clinical studies required to achieve the necessary indications for the marketed product. This article discusses biosimilarity and comparability as related scientific and regulatory concepts and the usefulness of clinical data for both.

Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial.

AIM: The aim of this study was to evaluate the effect on body weight and safety of subcutaneously administered recombinant leptin in obese adults and to evaluate whether the timing of recombinant leptin administration influences efficacy. METHODS: A randomized, double-blind, placebo-controlled, multicentre study was designed, comprising of a 3-week dietary lead-in followed by a 12-week leptin or placebo treatment period. A total of 284 overweight and obese (body mass index 27-37.0 kg/m(2)) predominantly white (98%) women (66%) and men (34%) with a mean (+/-s.d.) 46.8+/-10.4 years of age were randomized into three treatment groups with three matching placebo groups. Recombinant leptin was administered by subcutaneous injection [10 mg/morning, 10 mg/evening or 20 mg/day (10 mg twice daily)]. Patients were counselled at baseline to reduce dietary intake by 2,100 kJ/day (500 kcal/day), and dietary advice was reinforced every 2-4 weeks. RESULTS: No statistically significant change in body weight occurred with recombinant leptin treatment compared with placebo treatment in any treatment group. No clinically significant adverse effects were observed with the exception of an increase in injection-site reactions in patients treated with recombinant leptin (83%) vs. placebo (36%). CONCLUSIONS: Administration of recombinant leptin to an overweight and obese population, in addition to a mildly energy-restricted diet, was not efficacious in terms of weight loss at the doses and schedules studied. The hypothesis that nocturnal administration of recombinant leptin might have a specific effect on weight loss was not supported.

Effects of recombinant human leptin treatment as an adjunct of moderate energy restriction on body weight, resting energy expenditure and energy intake in obese humans.

We explored the effects of recombinant human leptin (rL) as an adjunct of mild energy restriction (2092 kJ/day less than needed) in the treatment of obese humans as part of a larger multicentre trial. In a double blind, randomised, placebo (P)-controlled design, the effects of 10 mg of rL once daily vs twice daily (rL OD/BID, by s.c. injection) upon body weight, resting energy expenditure (REE) and energy intake were compared. The study groups comprised 9 (P), 15 (rL OD) and 6 (rL BID) healthy subjects (body mass index 27.5-35 kg/m2). We observed in both groups treated with rL a decline of body weight. [2.8+/-1.1 kg (P), 5.2+/-0.9 kg (rL OD), 7.9+/-1.4 kg (rL BID), p < 0.035]. No significant effects of rL treatment upon energy intake or REE were observed. However, rL tended to reduce the decline of energy expenditure associated with energy restriction, whereas the tendency of energy intake to increase back to baseline levels in placebo-treated subjects was largely prevented in subjects treated with rL. Thus, rL appears to enhance the loss of body weight in obese humans in a dose-dependent fashion if prescribed as an adjunct of energy restriction. This effect might be mediated by rL ability to counteract the behavioural and metabolic adaptations that accompany weight loss attempts.

Refocusing HIV / AIDS interventions in Thailand: the case for male sex workers and other homosexually active men.

PIP: Although studies have shown that male sex workers in Thailand are at increased risk of HIV infection, no sustained strategy have so far been directed towards homosexually active men in the country. This paper brings together data from qualitative research carried out in Pattaya and Bangkok, with data generated during a bar-based intervention in Bangkok, to develop a taxonomy of sites in which the recruitment of male commercial sex can occur. The researchers also examined the sexual networks of Thai male sex workers and their clients in order to show the overlap of commercial and non-commercial male-male sex sites, and the intersection of male commercial sex with heterosexual sex. Previous efforts directed towards Thai male sex workers have been non-continuous; largely restricted to high-profile tourist areas; have not acknowledged the importance of recreational sex; and have not built up a capacity for ongoing intervention. With a change of focus, interventions targeted at sex workers could reduce the risks of HIV infection among organized and freelance sex workers as well as their commercial and male and female casual sex partners. Foremost, however, is the need to commit to well planned and long range interventions directed by and at male sex workers.^ieng

Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial.

CONTEXT: The protein hormone leptin is important to the homeostatic regulation of body weight. Treatment with exogenous leptin may affect weight loss. OBJECTIVE: To determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean and obese adults. DESIGN: A randomized, double-blind, placebo-controlled, multicenter, escalating dose cohort trial conducted from April 1997 to October 1998. SETTING: Four university nutrition and obesity clinics and 2 contract clinical research clinics. PARTICIPANTS: Fifty-four lean (body mass index, 20.0-27.5 kg/m2; mean [SD] body weight, 72.0 [9.7] kg) and 73 obese (body mass index, 27.6-36.0 kg/m2; mean [SD] body weight, 89.8 [11.4] kg) predominantly white (80%) men (n = 67) and women (n = 60) with mean (SD) age of 39 (10.3) years. INTERVENTIONS: Recombinant methionyl human leptin self-administered by daily morning subcutaneous injection (0 [placebo], 0.01, 0.03, 0.10, or 0.30 mg/kg). In part A, lean and obese subjects were treated for 4 weeks; in part B, obese subjects were treated for an additional 20 weeks. Lean subjects consumed a eucaloric diet to maintain body weight at the current value, and obese subjects were prescribed a diet that reduced their daily energy intake by 2100 kJ/d (500-kcal/d) from the amount needed to maintain a stable weight. MAIN OUTCOME MEASURES: Body weight, body fat, and incidence of adverse events. RESULTS: Weight loss from baseline increased with increasing dose of leptin among all subjects at 4 weeks (P = .02) and among obese subjects at 24 weeks (P = .01) of treatment. Mean (SD) weight changes at 4 weeks ranged from -0.4 (2.0) kg for placebo (n = 36) to -1.9 kg (1.6) kg for the 0.1 mg/kg dose (n = 29). Mean (SD) weight changes at 24 weeks ranged from -0.7 (5.4) kg for the 0.01 mg/kg dose (n = 6) to -7.1 (8.5) kg for the 0.30 mg/kg dose (n = 8). Fat mass declined from baseline as dose increased among all subjects at 4 weeks (P = .002) and among obese subjects at 24 weeks of treatment (P = .004); more than 95% of weight loss was fat loss in the 2 highest dose cohorts at 24 weeks. Baseline serum leptin concentrations were not related to weight loss at week 4 (P = .88) or at week 24 (P = .76). No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects. CONCLUSIONS: A dose-response relationship with weight and fat loss was observed with subcutaneous recombinant leptin injections in both lean and obese subjects. Based on this study, administration of exogenous leptin appears to induce weight loss in some obese subjects with elevated endogenous serum leptin concentrations. Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted.

Hepatic and peripheral glucose metabolism in intensive care patients receiving continuous high- or low-carbohydrate enteral nutrition.

BACKGROUND: The suppression of endogenous glucose production during parenteral nutrition is impaired in critically ill patients. It is, however, unknown whether enteral administration of carbohydrates, which normally promote hepatic glucose uptake, improves hepatic glucose metabolism in such patients. METHODS: We studied two groups of 7 patients during a 3-day continuous isocaloric enteral nutrition. A high-carbohydrate, low-lipid (EN-C) or a high-lipid, low-carbohydrate (EN-L) nutrient mixture was administered. RESULTS: Endogenous glucose production assessed with [2H7]glucose was similarly increased in both groups, indicating absence of its suppression by carbohydrate feeding. Gluconeogenesis estimated from [13C]glucose synthesis during [13C]bicarbonate infusion also was not suppressed by EN-C compared with EN-L. Systemic appearance of exogenous glucose was monitored by enteral infusion of [6,6-2H]glucose and was not different from the rate of glucose equivalent administered enterally, indicating no significant hepatic uptake of glucose in both groups. Plasma glucose and insulin concentrations were slightly higher with EN-C, although not significantly, and plasma triglycerides were similar in both groups. Both nutrition formulas were well tolerated clinically. CONCLUSIONS: These results indicate that enteral carbohydrate administration, whatever its quantity, fails to suppress endogenous glucose production and to promote net splanchnic glucose uptake in critically ill patients.

Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma.

BACKGROUND: Infections are an important cause of morbidity and mortality in patients with multiple trauma. Studies in both animals and human beings have suggested that glutamine-enriched nutrition decreases the number of infections. METHODS: Patients with multiple trauma with an expected survival of more than 48 h, and who had an Injury Severity Score of 20 or more, were randomly allocated glutamine supplemented enteral nutrition or a balanced, isonitrogenous, isocaloric enteral-feeding regimen along with usual care. Each patient was assessed every 8 h for infection, the primary endpoint. Data were analysed both per protocol, which included enteral feeding for at least 5 days, and by intention to treat. FINDINGS: 72 patients were enrolled and 60 received enteral feeding (29 glutamine-supplemented) for at least 5 days. Five (17%) of 29 patients in the glutamine-supplemented group had pneumonia compared with 14 (45%) of 31 patients in the control group (p<0.02). Bacteraemia occurred in two (7%) patients in glutamine group and 13 (42%) in the control group (p<0.005). One patient in the glutamine group had sepsis compared with eight (26%) patients in the control group (p<0.02). INTERPRETATION: There was a low frequency of pneumonia, sepsis, and bacteraemia in patients with multiple trauma who received glutamine-supplemented enteral nutrition. Larger studies are needed to investigate whether glutamine-supplemented enteral nutrition reduces mortality.

Predicting early nonelective hospital readmission in nutritionally compromised older adults.

This study determined predictors of early nonelective hospital readmission in 92 (49 women and 43 men) nutritionally compromised Medicare patients. Subjects ranged in age from 65 to 92 y and represented patients hospitalized previously for medical or surgical services. The study used a repeated-measures design of multiple variables representing demographics, anthropometric and clinical values, and functional status. Data were collected during hospitalization and during home visits at 1 and 3 mo postdischarge. There were 26 readmissions, making the 4-mo nonelective readmission rate 26%. Subjects who were readmitted nonelectively were compared with those not readmitted. Univariate analyses suggested strong relations between readmission outcome and serum albumin, total lymphocyte count, change in weight, and change in white blood cell count. Sociodemographic variables were less useful in predicting readmission than were measurements of patients' clinical status. Measurements of change in clinical variables were generally more predictive of readmission than was any one single measurement. Multivariate-logistic-regression analyses suggested a model consisting of change in weight and change in serum albumin from hospitalization to 1 mo after discharge as being highly predictive of early nonelective readmission. Individuals with any amount of weight loss and no improvement in albumin concentrations during the first month after hospitalization were at a much higher risk of readmission than were those who maintained or increased their postdischarge weight and had repleted their serum albumin concentrations. More study is warranted to clarify whether routine monitoring of changes in weight and serum albumin after hospitalization is appropriate in older adults.

Intestinal transit and absorption of soy protein in dogs depend on load and degree of protein hydrolysis.

Soy protein, in both intact and hydrolyzed forms, is widely used as the nitrogen source in infant and adult formulas. This protein is also consumed in vast quantities worldwide as soybean-based food products. Digestion is the rate-limiting step in the assimilation of proteins from the gut. As a result, intestinal transit must be slowed when a higher load of protein is available or when this nutrient is delivered in the intact rather than hydrolyzed form. However, little information is available on the effect of load and degree of hydrolysis of soy protein on intestinal transit and protein absorption. To test the hypothesis that inhibition of intestinal transit and protein absorption depend on the load of soy protein and the state of hydrolysis of this nutrient, we compared intestinal transit and protein absorption in dogs equipped with duodenal and midintestinal fistulas during intestinal perfusion with 0, 50, 100, or 200 g/L solutions of intact soy protein versus 0, 100, 200, 300, or 400 g/L solutions of hydrolyzed soy protein. We found that intestinal transit was slowed in a load-dependent fashion by intact (P < 0.001) and hydrolyzed (P < 0.05) soy protein. Soy protein inhibited intestinal transit more potently in the intact than hydrolyzed form (P < 0.05). A greater amount of protein was absorbed by the proximal half of the small intestine when soy protein was delivered in the hydrolyzed than intact form (P < 0.05), and the efficiency of protein absorption was maintained at a high and nearly constant level of 82.6 to 87.4% for intact soy protein and 89.0 to 92.3% for hydrolyzed soy protein. We conclude that in dogs intestinal transit and absorption of soy protein depend on the load and the degree of protein hydrolysis.

Protein absorption depends on load-dependent inhibition of intestinal transit in dogs.

Ileal perfusion of protein slows intestinal transit. Because optimal absorption of nutrients requires adequate time in contact with the mucosa, slowed intestinal transit may increase protein absorption by increasing the residence time of nutrients in the small intestine. Although protein supplements are routinely added to enteral feeding to correct protein malnutrition, little information is available on the effect of increasing the load of protein on intestinal transit and the efficiency of protein absorption. In six dogs equipped with duodenal and midintestinal fistulas, intestinal transit and the efficiency of protein absorption (percentage protein absorbed as estimated from the output of midintestinal fistula) were compared during intestinal perfusion with 0-, 50-, 100-, and 200-g/L solutions of a whey-based protein supplement. We found that intestinal transit slowed in a load-dependent fashion (P < 0.05); the amount of protein absorbed within the proximal one-half of the small intestine increased in a load-dependent fashion (P < 0.05) as intestinal transit slowed, and the percentage protein absorbed (reflecting the efficiency of protein absorption) was maintained at a high and nearly constant value of 66.5-72.5% across protein loads of 9-36 g. We conclude that enhanced protein absorption is associated with a load-dependent inhibition of intestinal transit.

Malnutrition and clinical outcomes: the case for medical nutrition therapy.

Malnutrition is not a new or a rare problem. In studies involving more than 1,327 hospitalized adult patients, 40% to 55% were found to be either malnourished or at risk for malnutrition, and up to 12% were severely malnourished. Surgical patients with likelihood of malnutrition are two to three times more likely to have minor and major complications as well as increased mortality; and their length of stay can be extended by 90% compared with the stay of well-nourished patients. Hospital charges are reported to be from 35% to 75% higher for malnourished patients than for well-nourished patients. Obtaining data to assess the nutritional status of patients is essential to optimal patient care, especially for patients at high risk for malnutrition. Nutrition assessment can be done with readily available and relatively inexpensive methods. But it is not enough to assess and identify malnutrition. Outcomes are improved and costs are saved only when appropriate intervention follows. This article identifies many well-conducted, published studies that support the findings that health outcomes of malnourished patients can be improved and that overall use of resources can be reduced by nutrition counseling, oral diet and oral supplements, enteral formula delivered via tube, and parenteral nutrition support via central or peripheral line. Early nutrition assessment and appropriate nutrition intervention must be accepted as essential for the delivery of quality health care. Appropriately selected nutrition support can address the problem of malnutrition, improve clinical outcomes, and help reduce the costs of health care.

Amino acid losses during hemodialysis: effects of high-solute flux and parenteral nutrition in acute renal failure.

BACKGROUND: During standard hemodialysis, amino acid losses are substantial, amounting to 6 to 9 g per treatment. When these nutritional supplements are infused during dialysis, losses are increased, but a net positive balance can be achieved if the infusion rate is high enough. High-flux dialyzers, used with increasing frequency in modern dialysis centers because of their more permeable synthetic membranes, should cause further amino acid losses; however, the increase has not been measured, and the effect on plasma levels has not been examined. Assessment of net balance requires measurement of blood concentrations as well as of clearance. METHODS: To quantitate the effect of high-flux dialysis on amino acid balance, we measured clearances, plasma levels, and losses of individual amino acids during hemodialysis in patients with acute renal failure who required daily parenteral nutrition. RESULTS: Nearly all predialysis amino acid levels in plasma were within the normal range, probably because of control of uremia with prior dialyses and from continuous infusion. In paired studies, clearances were higher (150 +/- 15 mL/min vs 107 +/- 11 mL/min, p < .01), and levels fell more at mid-dialysis with high-flux membranes (28% +/- 5%) than with conventional cellulosic membranes (4 +/- 5%, p < .05). Mean losses of amino acid were 5.2 +/- 0.6 g per conventional dialysis, representing 60% of the total infused, and 7.3 +/- 1.8 g per high-flux dialysis, or 80% of the simultaneous infusion. Fractional losses decreased at higher infusion rates, but losses of individual amino acids varied from one fourth to more than 10 times the amount infused. Compared with other small solutes, plasma levels were relatively well maintained even during high-flux dialysis, a factor that enhanced removal by the dialyzer. Total balance depended more on the infusion rate than on the dialysis membrane. CONCLUSIONS: These studies show that positive balance can be achieved with concurrent infusion during dialysis, especially at higher amino acid delivery rates. High-flux dialysis causes a greater disturbance of amino acid equilibrium than conventional dialysis does, but 24-hour gains far exceeded losses in the dialysate for most of the amino acids.