Aid when 'there is nothing left to offer': Experiences of palliative care and palliative care needs in humanitarian crises.

Access to palliative care, and more specifically the alleviation of avoidable physical and psychosocial suffering is increasingly recognized as a necessary component of humanitarian response. Palliative approaches to care can meet the needs of patients for whom curative treatment may not be the aim, not just at the very end of life but alleviation of suffering more broadly. In the past several years many organizations and sectoral initiatives have taken steps to develop guidance and policies to support integration of palliative care. However, it is still regarded by many as unfeasible or aspirational in crisis contexts; particularly where care for persons with life threatening conditions or injuries is logistically, legally, and ethically challenging. This article presents a synthesis of findings from five qualitative sub-studies within a research program on palliative care provision in humanitarian crises that sought to better understand the ethical and practical dimensions of humanitarian organizations integrating palliative care into emergency responses. Our multi-disciplinary, multi-national team held 98 in-depth semi-structured interviews with people with experiences in natural disasters, refugee camps in Rwanda and Jordan, and in Ebola Treatment Centers in Guinea. Participants included patients, family members, health care workers, and other staff of humanitarian agencies. We identified four themes from descriptions of the struggles and successes of applying palliative care in humanitarian settings: justification and integration of palliative care into humanitarian response, contextualizing palliative care approaches to crisis settings, the importance of being attentive to the 'situatedness of dying', and the need for retaining a holistic approach to care. We discuss these findings in relation to the ideals embraced in palliative care and corresponding humanitarian values, concluding that palliative care in humanitarian response is essential for responding to avoidable pain and suffering in humanitarian settings.

A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project.

BACKGROUND: There have been no major advances in tuberculosis (TB) drug development since the first East African/British Medical Research Council short course chemotherapy trial 35 years ago. Since then, the landscape for conducting TB clinical trials has profoundly changed with the emergence of HIV infection, the spread of resistant TB bacilli strains, recent advances in mycobacteriological capacity, and drug discovery. As a consequence questions have arisen on the most appropriate approach to design and conduct current TB trials. To highlight key issues discussed: Is a superiority, equivalence, or non-inferiority design most appropriate? What should be the primary efficacy outcome? How to consider re-infections in the definition of the outcome? What is the optimal length of patient follow-up? Is blinding appropriate when treatment duration in test arm is shorter? What are the appropriate assumptions for sample size calculation? METHODS: Various drugs are currently in the development pipeline. We are presenting in this paper the design of the most recently completed phase III TB trial, the OFLOTUB project, which is the pivotal trial of a registration portfolio for a gatifloxacin-containing TB regimen. It is a randomized, open-label, multicenter, controlled trial aiming to evaluate the efficacy and safety of a gatifloxacin-containing 4-month regimen (trial registration: ClinicalTrial.gov database: NCT00216385). RESULTS: In the light of the recent scientific and regulatory discussions, we discuss some of the design issues in TB clinical trials and more specifically the reasons that guided our choices, in order to best answer the trial objectives, while at the same time satisfying regulatory authority requirements. CONCLUSION: When shortening TB treatment, we are advocating for a non-inferiority, non-blinded design, with a composite unfavorable endpoint assessed 12 months post treatment completion, and added trial procedures specifically aiming to: (1) minimize endpoint unavailability; and (2) distinguish between relapse and re-infection.

A semimechanistic pharmacokinetic-enzyme turnover model for rifampin autoinduction in adult tuberculosis patients.

The currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters · h⁻¹ at the first dose, increased 1.82- and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction.