Standard of care, institutional obligations, and distributive justice.

The problem of standard of care in clinical research concerns the level of treatment that investigators must provide to subjects in clinical trials. Commentators often formulate answers to this problem by appealing to two distinct types of obligations: professional obligations and natural duties. In this article, I investigate whether investigators also possess institutional obligations that are directly relevant to the problem of standard of care, that is, those obligations a person has because she occupies a particular institutional role. I examine two types of institutional contexts: (1) public research agencies - agencies or departments of states that fund or conduct clinical research in the public interest; and (2) private-for-profit corporations. I argue that investigators who are employed or have their research sponsored by the former have a distinctive institutional obligation to conduct their research in a way that is consistent with the state's duty of distributive justice to provide its citizens with access to basic health care, and its duty to aid citizens of lower income countries. By contrast, I argue that investigators who are employed or have their research sponsored by private-for-profit corporations do not possess this obligation nor any other institutional obligation that is directly relevant to the ethics of RCTs. My account of the institutional obligations of investigators aims to contribute to the development of a reasonable, distributive justice-based account of standard of care.

What is the current and future status of conventional amphotericin B?

Amphotericin B deoxycholate has been the 'gold standard' treatment for invasive fungal infections for over 40 years. Driven to improve on the renal toxicity of amphotericin B deoxycholate, extensive pharmaceutical research has led to the development of several new antifungals including lipid formulations of amphotericin B, broad-spectrum azoles and echinocandins. Compared with amphotericin B deoxycholate, the lipid formulations of amphotericin B (amphotericin B lipid complex, amphotericin B colloidal dispersion and liposomal amphotericin B) share distinct advantages in improved drug safety, in particular reduced incidence and severity of amphotericin B deoxycholate-related nephrotoxicity. However, the lipid formulations of amphotericin B are significantly more expensive than amphotericin B deoxycholate and, as for many of these new antifungals, there are as yet insufficient published studies to guide clinicians. This paper examines aspects of safety, efficacy, and health economic data for the lipid formulations of amphotericin B in particular, in order to provide a rationale to justify substituting amphotericin B deoxycholate with the lipid formulations of amphotericin B.

Progress in the treatment of a neglected infectious disease: visceral leishmaniasis.

Visceral leishmaniasis (kala-azar) is a disseminated intracellular protozoal infection. Most cases (90%) occur in the rural regions of five countries: India, Sudan, Nepal, Bangladesh and Brazil. As with other infectious diseases embedded in high-level poverty, developing and/or delivering new treatments for visceral leishmaniasis had been painfully slow or nonexistent. However, despite persistent unresolved obstacles (e.g., drug affordability), renewed interest in visceral leishmaniasis and numerous successful treatment trials have combined to turn a therapeutic corner in the past 5 years, yielding new alternatives to conventional pentavalent antimony. Advances include the use of low-cost generic pentavalent antimony, rediscovery of amphotericin B, short-course regimens via lipid formulations of amphotericin B, retesting injectible paromyomycin and, of clear-cut importance, identifying miltefosine (Impavido, Zentaris) as the first effective oral therapy for this neglected disease.

Efficacy, safety and cost-effectiveness of Amphotericin B Lipid Complex (ABLC): a review of the literature.

Amphotericin B Lipid Complex (ABLC) was the first lipid-based formulation of amphotericin B (AmB) to be developed, it was designed to provide a less toxic alternative to conventional AmB without compromising efficacy. Preclinical and early clinical data relating to ABLC have been presented in previous reviews. This paper reviews more recent published data on the efficacy, safety and cost-effectiveness of ABLC. All published manuscripts and conference abstracts were searched on MEDLINE, BIOL and SCIN for the period between January 1997 and August 2003. Comparative and non-comparative studies of ABLC are usually mild or moderate and are manageable were considered. Comparative studies and additional data from non-comparative studies suggest that ABLC 5 mg/kg/day is safe and effective for the treatment of documented or suspected systemic fungal infections in adults and children who are refractory to or intolerant of conventional AmB. ABLC is effective against a wide range of pathogens and efficacy is at least as good as conventional AmB or the other lipid-based formulations. The safety profile of ABLC is improved compared with conventional AmB; ABLC is less nephrotoxic than conventional AmB and can be given safely to patients with pre-existing renal impairment. The most commonly reported adverse effects are transient infusion-related events, including chills, fever, nausea and vomiting, which with premedication. Comparative studies suggest that ABLC is a cost-effective treatment option compared with conventional AmB or other lipid-based formulations of amphotericin B.

Liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients.

Liposomal amphotercin B was compared with conventional amphotericin B for empirical antifungal therapy in febrile neutropenic patients in a randomized, double-blind, multicentre trial. Using a composite end-point, the two drugs were equivalent in overall efficacy. However, the liposomal amphotericin B treatment group had fewer proven fungal infections, fewer infusion-related side effects and less nephrotoxicity. Patient data from that study were analysed to compare the pharmacoeconomics of liposomal versus conventional amphotericin B therapy. Itemized billing data from 414 patients were collected and analysed. Hospital costs from first dose were significantly higher for all patients who received liposomal amphotericin B ($48,962 versus $43,183, P = 0.02). However, hospital costs were very sensitive to the cost of the study medication ($39,648 versus $43,048, when acquisition costs are not included, P = 0.4). Using decision analysis models and sensitivity analyses to vary the cost of study medications and risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients, and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients. Therefore, the drug acquisition costs and the risk of nephrotoxicity are important factors in determining the cost-effectiveness of liposomal amphotericin B as empirical therapy in persistently febrile neutropenic patients. In a recent randomized double-blind study comparing liposomal amphotericin B at 3 or 5 mg/kg/day with amphotericin B lipid complex (ABLC) 5 mg/kg/day as empirical antifungal treatment in patients with febrile neutropenia, liposomal amphotericin B was associated with less toxicity than ABLC, both in terms of infusion-related reactions and nephrotoxicity. The incidence of study drug discontinuation due to toxicity was: liposomal amphotericin B 3 mg/kg/day, 14%; liposomal amphotericin B 5 mg/kg/day, 15%; and ABLC, 42% (P < 0.001).

Treatment of antimony-unresponsive Indian visceral leishmaniasis with ultra-short courses of amphotericin-B-lipid complex.

High cost is the principal drawback of treating visceral leishmaniasis (VL; kala-azar) with any of the new lipid formulations of amphotericin B. The aim of the present study was to see if the costs of treatment with such drugs could be reduced by using ultra-short courses. Amphotericin-B-lipid complex (ABLC) was given to 77 Indian patients with antimony-unresponsive VL, either as a single infusion of 5 mg/kg (Group A) or two infusions, each of 5 mg/kg, given 5 days apart (Group B) or on consecutive days (Group C). Other than the anticipated higher fever and chills, treatment was well-tolerated. On day 19 after first infusion, 72 patients were considered apparent cures: 24 (89%) of the 27 in Group A; all 24 (100%) in Group B; and 24 (92%) of the 26 patients in Group C. Six months after treatment, 19 (70%) of 27 in Group A, 19 (79%) of 24 in Group B, and 21 (81%) of 26 in Group C were healthy, relapse-free and considered definitive cures. These cure rates were not statistically different. All 18 treatment failures (five initial non-responders and 13 relapses) were cured after treatment with a 5-day course of ABLC at a higher dose (10-15 mg/kg.day). In a related analysis of hospital plus drug costs for treating antimony-unresponsive VL, short-course ABLC (1-5 days) was compared with conventional amphotericin B (0.75-1.0 mg/kg on alternate days over 30-34 days). This analysis, which included the cost of re-treatment, identified one short-course ABLC regimen with an overall estimated expense which was only modestly higher than that of amphotericin B. Together, the present results provide further support for the use of ABLC in the management of VL patients who fail antimony therapy.