David Barnett

Relative efficacy of drugs: an emerging issue between regulatory agencies and third-party payers

Drug regulatory agencies have traditionally assessed the quality, safety and efficacy of drugs, and the current paradigm dictates that a new drug should be licensed when the benefits outweigh the risks. By contrast, third-party payers base their reimbursement decisions predominantly on the health benefits of the drug relative to existing treatment options (termed relative efficacy; RE). Over the past decade, the role of payers has become more prominent, and time-to-market no longer means time-to-licensing but time-to-reimbursement. Companies now have to satisfy the sometimes divergent needs of both regulators and payers, and to address RE during the pre-marketing stages. This article describes the current political background to the RE debate and presents the scientific and methodological challenges as they relate to RE assessment. In addition, we explain the impact of RE on drug development, and speculate on future developments and actions that are likely to be required from key players.

A randomised trial to investigate the efficacy of magnesium sulphate for refractory ventricular fibrillation

Background: Ventricular fibrillation (VF) remains the most salvageable rhythm in patients suffering a cardiopulmonary arrest (CA). However, outcome remains poor if there is no response to initial defibrillation. Some evidence suggests that intravenous magnesium may prove to be an effective antiarrhythmic agent in such circumstances. Study hypothesis: Intravenous magnesium sulphate given early in the resuscitation phase for patients in refractory VF (VF after 3 DC shocks) or recurring VF will significantly improve their outcome, defined as a return of spontaneous circulation (ROSC) and discharge from hospital alive. Design: A randomised, double blind, placebo controlled trial. Pre-defined primary and secondary endpoints were ROSC at the scene or in accident and emergency (A&E) and discharge from hospital alive respectively. Setting, participants, and intervention: Patients in CA with refractory or recurrent VF treated in the prehospital phase by the county emergency medical services and/or in the A&E department. One hundred and five patients with refractory VF were recruited over a 15 month period and randomised to receive either 2–4 g of magnesium sulphate or placebo intravenously. Results: Fifty two patients received magnesium treatment and 53 received placebo. The two groups were matched for most parameters including sex, response time for arrival at scene and airway interventions. There were no significant differences between magnesium and placebo for ROSC at the scene or A&E (17% v 13%). The 4% difference had 95% confidence intervals (CI) ranging from −10% to +18%. For patients being alive to discharge from hospital (4% v 2%) the difference was 2% (95% CI –7% to +11%). After adjustment for potential confounding variables (age, witnessed arrest, bystander cardiopulmonary resuscitation and system response time), the odds ratio (95% CI) for ROSC in patients treated with magnesium as compared with placebo was 1.69 (0.54 to 5.30). Conclusion: Intravenous magnesium given early in patients suffering CA with refractory or recurrent VF did not significantly improve the proportion with a ROSC or who were discharged from hospital alive.

Interactions of endogenous and exogenous norepinephrine with alpha2 adrenoceptor binding sites in rat cerebral cortex

The specific binding of (3H)yohimbine to alpha 2 adrenoceptors in rat cerebral cortex varied significantly with methods of membrane preparation. Membranes prepared in a sucrose containing buffer showed markedly lower Bmax values than those prepared in hypotonic buffer without any change in affinity (Kd) for (3H)yohimbine. Higher concentrations of residual endogenous norepinephrine were found in sucrose prepared membranes. In the presence of exogenous norepinephrine (10(-8), 10(-7) M), membranes prepared in hypotonic buffer showed apparent reduced receptor densities similar to those observed in sucrose prepared cerebral membranes. The presence of exogenous norepinephrine did not produce any apparent change in the overall Kd for (3H)yohimbine. The depression of (3H)yohimbine binding capacities could, in all cases, be reversed by performing incubations in the presence of 200 mM NaCl and 10 microM Gpp(NH)p which synergistically dramatically reduce the affinity of norepinephrine for cerebral alpha 2 adrenoceptors. It is concluded, therefore, that the lower (3H)yohimbine binding capacities in sucrose prepared membranes appears to be due to the occupancy of receptor sites by residual norepinephrine in a pseudo non competitive manner. The reduced affinity of retained endogenous norepinephrine for the alpha 2 adrenoceptor, in the presence of Na+ and guanine nucleotides, would seem to be the cause of the apparent increase in (3H)yohimbine binding sites produced by these modulators in sucrose prepared membranes.

Endovascular stent-grafts for the treatment of abdominal aortic aneurysms: NICE technology appraisal guidance

The National Institute for Health and Clinical Excellence (NICE) guidance on the use of endovascular stent-grafts (EVAR) for the treatment of abdominal aortic aneurysms was published in February 2009.1 This technology appraisal guidance should be read in conjunction with the NICE interventional procedure guidance on stent-graft placement in abdominal aortic aneurysm (interventional procedure guidance 163).2 EVAR is recommended as a treatment option for patients with unruptured infra-renal abdominal aortic aneurysms, for whom surgical intervention (open surgical repair or endovascular aneurysm repair) is considered appropriate.nnThe decision on whether EVAR is preferred to open surgical repair should be made jointly by the patient and his/her clinician after assessment of a number of factors including:nnEVAR should only be performed in specialist centres by clinical teams experienced in the management of abdominal aortic aneurysms and with appropriate expertise in all aspects of patient assessment and the use of endovascular aortic stent-grafts.nnEndovascular aortic stent-grafts are not recommended for patients with ruptured aneurysms except in the context of research.nnThe appraisal committee first considered the evidence on the clinical effectiveness of EVAR for the treatment of unruptured infra-renal abdominal aortic aneurysms. Four randomised controlled trials (RCTs) were identified3 4 5 6 7 8 comparing EVAR with open surgical repair (OSR) and three registries,9 10 11 12 13 14 which indicated that EVAR had benefits in terms of reduced rates of operative and aneurysm-related mortality in the medium term. However, these findings were not accompanied by a reduction in all-cause mortality and were associated with increased rates of complications and re-interventions for EVAR compared with OSR.nnEvidence from clinical specialists …

α2-Adrenoceptor coupling to adenylate cyclase in adrenaline insensitive human platelets

Coupling of the alpha 2-adrenoceptor to adenylate cyclase was assessed in platelets from 3 groups of subjects: normal controls and patients with myeloproliferative disorders whose platelets were either sensitive or specifically insensitive to the aggregatory effects of adrenaline. The ability of adrenaline to induce the formation of a complex between the alpha 2-adrenoceptor and the inhibitory guanine nucleotide binding protein was examined in all three groups by assessment of the effect of mono and divalent cations and Gpp(NH)p on the displacement of [3H]yohimbine binding to platelet membranes by adrenaline. Coupling to adenylate cyclase was also assessed in separate studies of the inhibition by adrenaline of PGE1 stimulated cyclic AMP accumulation in whole platelets. Both the formation of the ternary complex and the inhibition by adrenaline of cyclic AMP accumulation was not significantly different in platelets sensitive or insensitive to adrenaline. These results suggest that inhibition of cyclic AMP alone does not explain the mechanisms of adrenaline induced platelet aggregation.

Human platelet α2-adrenoceptors: Relationship between radioligand binding studies and adrenaline-induced aggregation in normal individuals

Using the alpha 2-adrenoceptor selective radioligand [3H]yohimbine maximum binding capacities (Bmax), dissociation constants (KD), and the affinity (KI) of adrenaline for the binding sites were measured in platelets obtained from a group of 42 normal individuals. These results were compared with the efficacy of adrenaline induced aggregation in platelet rich plasma in the same subjects. Wide interindividual variation was found in Bmax values as measured in whole platelets (sites/platelet) or platelet lysates (fmol/mg protein) and in KI values for adrenaline displacement of [3H]yohimbine binding. Adrenalines ability to induce platelet aggregation measured as the concentration required to achieve half maximal aggregation assessed from dose-response curves showed similar interindividual variation. No correlation was found, however, between alpha 2-adrenoceptor status as assessed by radioligand binding studies and the functional studies. These results suggest that the present understanding of the relationship between alpha 2-adrenoceptor occupation and platelet aggregation may be incorrect.

The cancer technology appraisal programme of the UK's National Institute for Clinical Excellence

The National Institute for Clinical Excellence (NICE) was established to ensure faster and more equitable uptake of new technologies by the NHS, through the provision of guidance on clinical and cost-effectiveness. The treatment of cancer is one of the UK governments priority areas and a range of guidance products have been developed by NICE to support implementation of national plans for managing patients with cancer in England and Wales. In its first 3 years, NICEs main activity was the Technology Appraisals Programme and it has created considerable interest and some controversy. 15 (out of a total of 56) technology appraisals related to oncology have been completed and another four are in preparation. The open, transparent, and inclusive approach NICE has adopted in reaching its decisions highlights the difficult ethical issues that need to be addressed in seeking to balance individual desires with public-health requirements. In this review we describe the process of appraising technologies, and address the recent criticism of the appraisal programme with regard to treatment of patients with cancer.

Human platelet β2‐adrenoceptors: agonist‐induced internalisation and down‐regulation in intact cells

1 The effect of isoprenaline (10 μm at 37°C for 30 min) pretreatment on [125I]‐(—)‐pindolol ([125I]‐(—)‐Pin) binding to β2‐adrenoceptors on intact human platelets has been examined. 2 By use of saturation analysis, maximal binding capacity (Bmax) of [125I]‐(—)‐Pin binding in control and treated cells was assessed in the presence of 1 μm (—)‐propranolol or 1 μm (±)‐CGP 12177 which were taken to represent total or cell surface β‐adrenoceptors respectively. Assay incubations were performed at 37°C and 4°C, the latter to prevent recycling of internalised receptors. 3 Isoprenaline treatment resulted in an identical, highly significant, loss of binding sites (⋍ 25%) defined by (—)‐propranolol at both assay temperatures as compared to control cells. Binding sites identified in the presence of (±)‐CGP 12177 were reduced to a much greater extent (⋍ 70%), but this was only seen when assays were performed at 4°C. 4 Agonist‐induced changes in receptor numbers were concentration‐dependent with half maximal receptor loss occurring at an isoprenaline concentration of approximately 2 × 10−8 m. These effects were inhibited by the presence of a β‐adrenoceptor antagonist and absent if agonist pretreatment was performed at 4°C. 5 Recovery experiments showed that the isoprenaline‐induced reduction in total receptor number defined by (—)‐propranolol was irreversible whereas the reduction in cell surface receptors defined by (±)‐CGP 12177 was rapidly reversible (< 40 min). 6 These data suggest that isoprenaline treatment of intact human platelets causes redistribution of β2‐adrenoceptors. A proportion are sequestered away from the cell surface (internalised), becoming inaccessible to the hydrophilic ligand (±)‐CGP 12177. A smaller proportion defined by (—)‐propranolol are apparently totally lost from the cell (down regulated).

Subtype selective regulation of coupling of rat cardiac ß adrenoceptors to adenylate cyclase

There is now evidence from human studies to suggest that cardiac beta-adrenoceptor density and coupling to adenylate cyclase may be regulated in a subtype selective fashion. An animal model was used to investigate this further. Rats were infused for 6 days with the non-selective full agonist isoprenaline (n = 6) or the beta 1-selective partial agonist xamoterol (n = 6) with sham operated rats (n = 6) for control. beta-Adrenoceptor subtype density and coupling to adenylate cyclase were determined in left ventricular membranes. Isoprenaline infusion downregulated both beta 1- (30%) and beta 2- (63%) adrenoceptor subtypes with associated reduction in adenylate cyclase stimulation through both subtypes. Xamoterol did not downregulate either subtype, but selectively uncoupled beta 1-adrenoceptors. beta 1- and total beta-adrenoceptor-mediated stimulation of adenylate cyclase was reduced less by xamoterol than isoprenaline. We conclude that coupling of rat cardiac beta-adrenoceptors can be regulated in a subtype selective fashion and that the partial agonist xamoterol does not desensitise beta-adrenoceptor mediated stimulation of adenylate cyclase to the same extent as the full agonist isoprenaline.

Is the human platelet beta2 adrenoceptor coupled to adenylate cyclase

SummaryThe presence of beta2 adrenoceptors on the human platelet is well established although the coupling of this receptor to adenylate cyclase is disputed. In this study of highly purified platelets isoprenaline did not stimulate whole platelet cyclic AMP alone or in the presence of forskolin. Minimal contamination of the purified platelets (approximately 0.05%) with mononuclear white blood cells may lead to the spurious appearance of isoprenaline stimulated cAMP. These results confirm our previous findings of lack of coupling of the human platelet beta2 adrenoceptor to adenylate cyclase and indicate the importance of purity of preparation for platelet biochemical studies.