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Alemtuzumab (Millennium/ILEX).

Alemtuzumab, a lymphocyte-depleting humanized monoclonal antibody, is being developed by Millennium Pharmaceuticals Inc and ILEX Oncology for the potential treatment of chronic lymphocytic leukemia (CLL) [274580]. The utility of the compound for treating bone marrow (BM) stem cell transplantation-associated graft-versus-host disease (GVHD) [372946] and for ex vivo purging of BM to remove malignant T-cells [244056] is also being investigated. Additional potential therapeutic areas for which clinical trials are planned or ongoing include vasculitis, multiple sclerosis [288762] and organ transplantation [338304]. A Biologics License Application (BLA) was filed with the FDA in December 1999 by ILEX and Millennium [351523], [351524], [373873]. The FDA accepted the application for filing in February 2000 [355775] and returned a complete response letter in June 2000 [372172]. Millennium and ILEX submitted a response to the FDA in August 2000 [379766]. Alemtuzumab has received Fast Track designation [304771] and orphan drug status from the FDA [288762], and the drug was reviewed by the FDA's Oncologic Drugs Advisory Committee on 14 December, 2000 [387228]. The committee voted 14 to 1 to recommend accelerated approval of alemtuzumab for patients with CLL who have been treated with alkylating agents and who have failed fludarabine therapy [393778], [393894]. In March 2000, Millennium and ILEX also submitted a Marketing Authorization Application (MAA) for alemtuzumab to the European Agency for the Evaluation of Medicinal Products (EMEA) [363595]. In October 2000, EMEA accepted the MAA for alemtuzumab under the agency's centralized approval procedure [387228]. Alemtuzumab was originally synthesized by Herman Waldmann and colleagues at Cambridge University and licensed to Burroughs Wellcome (BW) via the British Technology Group (BTG) [162622]. BW conducted phase I and II trials for a broad range of indications, but then discontinued development because of disappointing results in phase II rheumatoid arthritis trials [326848]. In April 1997, LeukoSite licensed rights to the antibody from BTG for the treatment of CLL and prolymphocytic leukemia, plus an option to develop it for other indications. BW agreed to supply LeukoSite with intellectual property [244056], [326848]. In May 1997, LeukoSite entered into a joint venture with ILEX Oncology for the further development of alemtuzumab [245986]. By the end of 1999, Millennium acquired LeukoSite with commitment to pursue development of the compound through the joint venture Millennium & ILEX Partners LP [351523], [370237]. In August 1999, Schering AG and its US affiliate Berlex Laboratories obtained exclusive worldwide marketing rights for alemtuzumab, excluding Japan and East Asia. In the US, Berlex, Millennium and ILEX will divide profits from alemtuzumab sales equally [337702], [338837].

Alemtuzumab↗

Direct democracy and bioethical choices: voting life and death at the ballot box.

Direct democracy, the political process that enables citizens to draft, circulate, and enact laws, has become the refuge for grassroots organizations seeking statutory validation in a legislative arena perceived to be unresponsive or unfriendly to their concerns. One group of citizens, advocates for physician-aid-in-dying, has recently emerged on the national scene, sponsoring state ballot initiatives in three states and pledging to continue their quest for legalization of physician-assisted death throughout the country. In this Article, Professor Daar examines the interplay between direct democracy and regulation of end-of-life decision making. This examination reveals that lawmaking of physician-aid-in-dying, is no less susceptible to the ravages of political wrangling than is representative democracy. Professor Daar argues that direct democracy is best utilized as a spur to legislative action rather than as a replacement for the study and compromise unique to legislating through representative democracy. In addition, the author advocates recognition of a constitutionally protected liberty interest in choices surrounding death, thus providing a threshold level of protection to all citizens, not just those whose lawmakers or citizens are motivated to codify this fundamental right.

Bioethical Issues↗

Upside-down orbitopathy: unilateral orbital dependent-tissue oedema causing total visual loss.

The case is reported of a 24-year-old man who was involved in a road traffic accident and became trapped upside down with the right side of his face being the most dependent part of his body. Marked hemifacial tissue oedema was associated with right acute compressive orbitopathy and vascular compromise. Acute dysfunction of al orbital nerves was found on examination. Such neuropathy is usually related to the consequences of direct trauma, fractures or haemorrhage; however, computed tomography scanning demonstrated no evidence of orbital fracture or haemorrhage. Immediate anterior surgical orbital decompression was performed in the emergency room in addition to high dose intravenous steroids. Dependent orbtal tissue oedema is proposed as a mechanism of compressive orbitopathy with consequent ischaemic damage to all orbital nerves, total visual loss and complete ophthalmoparesis. Good recovery of other orbital nerves has occurred and the globe has reperfused. Despite intervention, no visual function has returned.

Accidents, Traffic↗

What is the preimplantation embryo?

We present results from our 'bioethical field studies', which explore and compare the views of experts, patients and the general public on the beginning of human life and the status of the preimplantation embryo in Germany. Using a qualitative and quantitative multi-method approach, we found crucial differences in the categorization of the beginning of human life within the expert group (representative samples of human geneticists n=104, ethicists n=168, midwives n=294, obstetricians n=147, paediatricians n=166), and between expert and lay samples (IVF couples n=108, high genetic risk couples n=324, general population n=1017). The majority of lay respondents as well as paediatricians and obstetricians chose nidation, the moment when the implantation of the fertilized egg into the uterus takes place, as the crucial boundary that marks the beginning of human life, whereas the majority of (female) human geneticists, ethicists and midwives voted for conception as the decisive point in time. The views of all groups on the status of the preimplantation embryo differed from the assumptions underlying German legislation (Embryo Protection Act). Religiousness and religious affiliation, gender, attitudes towards disabled people, post-material values and a present desire for a child were identified as independent factors influencing attitudes towards the preimplantation embryo in the population sample. The results are discussed within a broader philosophical and social science perspective of constructivism versus essentialism, proposing a truly interdisciplinary approach to such bioethical core issues as new reproductive technologies and the status of the preimplantation embryo.

Adolescent↗

Death--whose decision? Euthanasia and the terminally ill.

In Australia and Oregon, USA, legislation to permit statutory sanctioned physician-assisted dying was enacted. However, opponents, many of whom held strong religious views, were successful with repeal in Australia. Similar opposition in Oregon was formidable, but ultimately lost in a 60-40% vote reaffirming physician-assisted dying. This paper examines the human dilemma which arises when technological advances in end-of-life medicine conflict with traditional and religious sanctity-of-life values. Society places high value on personal autonomy, particularly in the United States. We compare the potential for inherent contradictions and arbitrary decisions where patient autonomy is either permitted or forbidden. The broader implications for human experience resulting from new legislation in both Australia and Oregon are discussed. We conclude that allowing autonomy for the terminally ill, within circumscribed options, results in fewer ethical contradictions and greater preservation of dignity.

Attitude of Health Personnel↗

Hyaluronidase (Vitrase)--ISTA: hyaluronidase--ISTA pharmaceuticals.

ISTA Pharmaceuticals (formerly Advanced Corneal Systems) has developed an ophthalmic injectable formulation of highly purified hyaluronidase [ovine hyaluronidase, Vitrase] for the initial treatment of vitreous haemorrhage and diabetic retinopathy. Hyaluronidase is a naturally occurring enzyme that digests certain forms of carbohydrate molecules called proteoglycans. The current medical treatment for vitreous haemorrhage is vitrectomy, an invasive surgical procedure that may result in future cataract formation, retinal detachment or other complications. There are currently no approved drug therapies for vitreous haemorrhage. ISTA believes that an injection of Vitrase causes the vitreous to liquefy, thereby promoting the clearance of vision-distorting blood. The elimination of blood helps to restore vision and provides an ophthalmologist with an unobstructed view of the retina, allowing the doctor to diagnose and treat the underlying cause of the hemorrhage. In mid-1997, Advanced Corneal Systems (now ISTA Pharmaceuticals) formed a Singapore subsidiary called Visionex to develop and market the company's technologies in Southeast Asia and China. In March 2000, ISTA completed the acquisition of Visionex. Also in March 2000, subsidiaries of Allergan obtained marketing, sales and distribution agreements from ISTA for Vitrase worldwide, except Mexico (until April 2004) and Japan. ISTA will split Vitrase profits equally with Allergan and receive royalties on sales in non-US countries. ISTA is responsible for all costs of product development, preclinical studies and clinical trials, of Vitrase and may receive up to 35 million US dollars in milestone payments from Allergan upon the achievement of specified regulatory and development objectives. In December 2001, Otsuka gained exclusive rights to develop, market and commercialise Vitrase in Japan. In July 2002, ISTA announced that it has entered into an agreement with Cardinal Health for the manufacture of commercial quantities of Vitrase. The agreement covers the US, Canada, Japan and the European Union. Cardinal Health will also provide manufacturing-related information for the US New Drug Application (NDA). Sophia Laboratories distribute Vitrase in Mexico. The US FDA designated Vitrase as a fast track product in October 1998, which means the FDA will facilitate the development and expedite the review of the product. Vitrase has being investigated in two multinational, randomised, placebo-controlled, phase III trials in patients with severe vitreous haemorrhage. One was conducted in the US, Mexico and Canada (North American trial) with an enrolment of 750 patients. The second trial was conducted in Europe, Brazil, Australia and South Africa and enrolled 556 patients. In March 2002, ISTA began unmasking the data, revealing that although preliminary efficacy results did not show any statistically significant improvement in the primary endpoint, clinically relevant improvements in visual acuity and a decrease in the density of vitreous haemorrhage were observed in patients treated with a 55IU dose of Vitrase, compared with placebo-treated patients. In December 2002, the FDA accepted the NDA for Vitrase for filing. The FDA's Dermatologic and Ophthalmic Drugs Advisory Committee reviewed the Vitrase NDA on 17 March 2003 and voted 8 to 4 that there was insufficient statistical evidence to support the use of Vitrasefor the treatment of vitreous haemorrhage. However, the Committee did recognise that in certain patient subgroups, the benefits of Vitrase therapy outweighed the potential risks. The FDA has recommended that ISTA provide additional analyses from the two pivotal phase III trials conducted. In April 2003, the FDA issued an approvable letter for Vitrase for the treatment of vitreous haemorrhage. ISTA anticipates that the FDA will complete its review of the Vitrase NDA anete its review of the Vitrase NDA and issue the results during the second half of 2003. In addition, ISTA plans to submit a marketing approval application with the European Medical Evaluation Agency (EMEA) in the first half of 2003. A phase II trial in Singapore was being conducted by Visionex. However, in March 2000, ISTA completed the acquisition of Visionex. In its Securities and Exchange Commission (SEC) filing, as at 31 December 2002, ISTA stated that the continued development of Vitrase for diabetic retinopathy will be dependent upon a number of factors including the FDA's evaluation of Vitrase for the treatment of vitreous hemorrhage, the successful completion of any additional clinical trials for the diabetic retinopathy, and the continuing assessment of the market opportunity for this indication compared with other product opportunities that ISTA may be pursuing at the time. ISTA is also developing hyaluronidase products for the treatment of cataracts (Keratase) and keratoconus (Keraform).

Clinical Trials as Topic↗

Court lifts ban on enforcing Miss. anti-abortion law.

A federal court order yesterday made Mississippi the first state to get permission under the Supreme Court's new abortion ruling to start enforcing a law designed to limit women's rights to end pregnancy. Without saying why, the 5th US Circuit Court of Appeals in New Orleans put into immediate effect a ruling it had issued just hours earlier permitting Mississippi to carry out an antiabortion criminal law that had been passed last year over the governor's veto. State prosecutors said they would start enforcing the law at midnight Saturday. They set that deadline after the appeals court refused a plea by 2 clinics and 2 doctors to delay its ruling for at least a month. The law requires doctors to wait for 24 hours to perform an abortion, with only a narrow exception for medical emergencies. It also requires doctors to give pregnant women advice--before they can get an abortion--about financial aid if they continue the pregnancy and have a baby, about the age of the fetus they are carrying, and about the medical risks of abortion and of carrying the pregnancy to term. The Mississippi case was the first one in which lawyers had a chance to debate the effect on other states laws of the Supreme Court's latest ruling about 5 weeks ago, in a Pennsylvania case. Lawyers challenging the Mississippi law contended that it is more restrictive than similar provisions of Pennsylvania antiabortion laws that the Supreme Court tentatively upheld in its June 29 decision. In the Pennsylvania ruling, the Supreme Court spelled out by a 5-4 vote a more relaxed constitutional standard for judging state abortion curbs. Under the Mississippi law, the 24-hour wait for an abortion would apply even in most medical emergencies confronted by a pregnant woman. The only time it would not apply was when the pregnancy threatened immediate loss of some bodily function. Pennsylvania's law would allow doctors more discretion in emergencies to go ahead with an abortion. The Mississippi law forbids doctors to avoid giving the mandated advice, even if the doctor believes that the advice itself posed a psychological risk to the woman. There is no "therapeutic exception" to the duty to give the advice, while there is in the Pennsylvania law. Although the advice mandated in Mississippi includes assurances that, if the pregnancy continues to birth, the father will be obliged to provide support, lawyers for the challengers offered evidence that only 5% of the women in Mississippi seeking child support from fathers get it. The appeals court in New Orleans said it would explain its action on the Mississippi law in a formal opinion later. Its 2-sentence order simply wiped out a federal judge's year-old order for forbidding Mississippi to enforce its law. The appeals court also gave no immediate explanation for refusing to postpone its ruling. Rachel Pine, a lawyer for the Center for Reproductive Law and Policy and one of the attorneys handling the Mississippi case, described the court orders as "step 1 in the fallout" from the Supreme Court's June 29 ruling. She predicted that court orders now in effect against state antiabortion laws "are going to be vacated, all across the country." Ms. Pine and other attorneys in the Mississippi case wanted the appeals court to send their case back to a trial judge, so they could try to challenge it anew as unconstitutional even under the latest Supreme Court ruling. They told the appeals court that the Mississippi law was different enough from the Pennsylvania law that it could not survive under the new standards.

Abortion, Induced↗

Pseudoneglect: a review and meta-analysis of performance factors in line bisection tasks.

An exhaustive qualitative (vote-counting) review is conducted of the literature concerning visual and non-visual line bisection in neurologically normal subject populations. Although most of these studies report a leftward bisection error (i.e., pseudoneglect), considerable between-study variability and inconsistency characterize this literature. A meta-analysis of this same literature is performed in which the total quantitative data set, comprising 73 studies (or sub-studies) and 2191 subjects, is analyzed with respect to 26 performance factors. The meta-analytic results indicate a significant leftward bisection error in neurologically normal subjects, with an overall effect size of between -0.37 and -0.44 (depending on integration method), which is significantly modulated to varying degrees by a number of additional task or subject variables. For example, visual bisection tasks, midsagittal-pointing tasks and tactile bisection tasks all lead to leftward errors, while kinesthetic tasks result in rightward errors. Tachistoscopic forced-choice testing methods reveal much greater estimates of bisection error (effect size = -1.32) than do manual method-of-adjustment procedures (effect size= -0.40). Subject age significantly modulates line bisection performance such that older subjects err significantly rightward compared to younger subjects, and to veridical line midpoint. Male subjects make slightly larger leftward errors than do female subjects. Handedness has a small effect on bisection errors, with dextrals erring slightly further to the left than sinistral subjects. The hand used to perform manual bisection tasks modulated performance, where use of the left hand lead to greater leftward errors than those obtained using the right hand. One of the most significant factors modulating bisection error is the direction in which subjects initiate motor scanning (with either eye or hand), where a left-to-right scan pattern leads to large leftward errors while a right-to-left scan pattern leads to rightward errors.

Adult↗

[Relapse prevention group therapy for paedophiles: French adaptation].

Psychotherapy for sex offenders has only very recently started to develop in France. The French law on compulsory treatment for sex offenders was voted in 1998, and many mental health practitioners are not trained to treat such patients yet. In our ambulatory forensic consultation, sex offenders have been treated since 1992 and group psychotherapy has been offered to them since 1994. Our first therapeutic models were the North-American behavioural-cognitive therapy and Pithers' relapse prevention model. Behavioural-cognitive theory describes paedophilia as an acquired sexual preference maintained by positive reinforcement. Pithers (1990) considered that relapse only occurs in high-risk situations, and that high-risk situations always come after offence precursors. In North America, relapse prevention consists in helping paedophiles spot their high-risk situations and offence precursors, and enhance their skills to cope with such situations or to prevent them. Therapy programs were developed according to these models, aiming to help offenders develop such skills, ie empathy, social skills, cognitive restructuring, self-esteem, etc. Trying to apply these therapy programs in France, our team quickly realised that we would have to adapt them to French culture. On the one hand, behavioural-cognitive theory did not seem satisfactory enough in explaining paedophilic behaviour and paedophilic preference. On the other hand, behavioural-cognitive therapy made patients into children too much and increased resistance. Therapy based on programs seemed too rigid for French patients and therapists, and we often felt we were working on an issue that would have been much more accurate to work on a few sessions earlier, when this issue was spontaneously brought up by a patient. We believe change occurs all the more as issues are worked on at the right moment for the patient. Moreover, on a cultural point of view, we also realised the use of programs in psychotherapy was difficult to accept in France both by patients and therapists, as our culture is strongly influenced by psychoanalysis, especially free association. The use of a plethysmograph was also impossible in our country. We thus decided to use Pithers' relapse prevention model but to let our patients free to speak, so our therapy was not a program. Offences were analysed according to Pithers' ideas about high-risk situations and offence precursors. Most of the sessions were non-directive, but therapists offered each patient to work on his offence when they believed it was the right moment. Important issues (such as empathy, cognitive distortions, emotional control, etc.), were tackled as they came up, which seemed easier and less rigid as sessions were linked to patients' current pre- occupations. Post-group meetings enabled therapists to draw themes that seemed important to work on with each patient (empathy, consequences on victims, anger, cognitive distortions, emotional expression, relational issues, self-esteem, intimacy...). These issues were discussed the next time they were raised by the group. We were interested to notice that all important issues came up spontaneously from the group during the sessions as long as patients were free to share their concerns, without therapists having to set issues beforehand. Two case studies illustrate our method. Bernard was 40 when he first came to our consultation. Originally a teacher, he was dismissed and became a marketing man after being sentenced to five years of prison for sex offences on two 6-year-old girls. Bernard relapsed a few years after he got out of prison by sexually offending two girls, aged 10 and 13. At our first interview, Bernard had cognitive distortions about sexual education and always avoided sexually explicit words to describe the offences. He did not realise the consequences of his acts on the victims, but said he wanted to be treated because he felt lonely. He first described a sexual preference for adult women, but progressively aknoledged feeling attracted to female teenagers. He did not know why the offences occurred at such a moment in his life, and had no idea of his high-risk situations nor of his offence precursors. Bernard often confused his need for sex and his need for affection. After four years' participation to our relapse prevention group therapy, Bernard has clarified his sexual preferences : he has always been mostly attracted to girls from 6 to 10 years old. He has also always been attracted to women younger than him, and now seems to be mostly aroused by female teenagers. Working on his offences has helped him identify his high-risk situations and the strategies he used to get close to his victims and to be trusted by them and their single mothers. Bernard often offended when he was feeling lonely and rejected, after a break-up with a partner. Twice during these four years, Bernard found himself in such high-risk situations, but managed to stop before relapsing. However, empathy towards victims is still difficult to develop for Bernard. Neither has he yet managed to build a new relationship with a woman, as he still seems to suffer from an unhappy love affair he went through several years ago. This case study shows one of the limits of Pithers' relapse prevention model, if it is used mechanically. Indeed, we should logically have spotted as high-risk situations for Bernard interactions with 6 to 10 year-old girls. Helping him face his past and present sexual fantasies led Bernard realise his high-risk situations were now mainly about teenage girls, even if he had mostly been attracted to younger girls earlier in his life. After 2 to 3 years of therapy, we have quite often noticed this kind of evolution in sexual preferences in paedophiles, their preferences changing towards teenagers or young adults. In France, mental health professionals are often reluctant to follow sex offenders because of negative counter-transference and lack of specific training. However, first changes often occur quite quickly in paedophiles when they are offered group therapy. The group makes it easier to confront paedophiles to the reality of their offence and of their sexual fantasies. These patients often express being very relieved after the first sessions, as the group therapy is generally their first opportunity to express their feelings, sexual fantasies and thoughts about paedophilia. Pithers' model, used within a group were patients are free to speak in a human, warm and confronting atmosphere, seems clinically accurate and effective in helping paedophiles in France. We now need studies to check therapy effectiveness on relapse and to understand which therapy factors are efficient on sex offenders.

Adult↗

[Health care systems and impossibility theorems].

Health care systems, amongst the most complicated systems that serve mankind, have been in turmoil for many years. They are characterized by widespread dissatisfaction, repeated reforms and a general perception of failure. Is it possible that this abominable situation derives from underlying causes, which are inherent to the most basic elements of these systems? Those elements compromise the use of words and definitions in the formulation of their principles and their way of action, in their logical structure as well as in the social order in which they exist. An in-depth investigation of these elements raises findings that may negate the basic feasibility of the success of such complex systems, as currently known in the western world. One of the main elements of the democratic regime is its system of decision/choice making, i.e. the majority vote. But, already in the nineteenth century, it was discovered that a majority was an intransitive ordering and did not produce a consistent definition of a preference. The Marquis of Condorcet in his famous 1785 "Essai sur l'application de l'analyse a la probabilite des decisions rendues a la plurite des voix", clearly demonstrated that majority decisions might lead to intransitivity and an indeterminancy in social choices. On the basis of his discoveries, it was later shown that legislative rules may lead to the choice of a proposal that is actually opposed by the majority, or to a deadlock and therefore, to socially undesirable implications. Subsequent to these theories of Condorcet, which became known as "The Paradox of Condorcet", many papers were published in the 19th and 20th centuries regarding the issue of problems dealing with individual preferences leading to social order--a complex procedure of, amongst others, aggregation in a defined axiomatic framework. During the twentieth century it became astoundingly manifest that certain issues, although correctly attacked logically, could not be resolved. Two such famous results are Kurt Godel's seminal paper in 1931: "Ueber formal unentscheidbare Saetze der Principia Mathematica and verwandter System I" and Arrow's Nobel Prize winning "Impossibility Theorem" (Social Choice and Individual Values, 1951). Godel showed, unequivocally, that there is an enormous gap between what is being perceived as truth and what in fact can be proven as such. Arrow showed that the translation of individual preferences into a social order is impossible--except in a dictatorship. The unsolved controversies concerning the desirable or ideal structure of health care systems are impinged upon by these findings generally, and, in the case of the impossibility theorem, also directly. There is the impossibility of aggregating preferences and, at a deeper level, the impossibility of defining certain fundamental values, coupled with the problematic use of certain words, the absence of the possibility of creating, on a logically defined base, a complex system, complete and comprehensive in its own right. This is added to the fact that according to the elaboration by Stephen Wolfram in "A New Kind of Science", it is not easy to reduce complicated systems to simple components and to predict the continuation of their development even from simple basic laws without complicated calculations. All of these factors impede the construction of satisfying health care systems and leave obvious problems which overshadow the structure and the operation of health care systems.

Delivery of Health Care↗

Trabectedin: Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766.

Trabectedin [Ecteinascidin 743, Yondelis, ET 743, NSC 684766] is a tetrahydroisoquinoline alkaloid derived from the Caribbean marine tunicate, Ecteinascidia turbinata. The drug is being developed by PharmaMar (Zeltia) in partnership with Johnson & Johnson Pharmaceutical Research & Development LLC. It was synthetically isolated and developed by the University of Illinois and licensed to PharmaMar; the company has completed the hemisynthesis of agent. Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G(2) phase, while cells at the G(1 )phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. PharmaMar and Ortho Biotech Products (Johnson & Johnson) entered into an agreement in August 2001 for the joint development and commercialisation of trabectedin. PharmaMar retains commercialisation rights in Europe, including Eastern Europe. Ortho Biotech will market the product in the US, Japan and the rest of the world; Tibotec Therapeutics (a division of Ortho Biotech) will commercialise it in the US. PharmaMar will receive an initial payment from Ortho Biotech plus future milestone and royalty payments linked to development targets and sales; the upfront payment would be approximately 20 million US dollars with royalties contributing 10-20% of total sales of the drug. Although details of the licensing transaction for trabectedin were undisclosed, analysts estimate the figure to be around 100 million US dollars. Previously, PharmaMar signed an agreement granting Bristol-Myers Squibb the option to evaluate and develop as many as 12 of PharmaMar's marine-derived anticancer compounds on an exclusive worldwide basis. However, it appears that Bristol-Myers Squibb had chosen not to exercise the option. Trabectedin is undergoing clinical trials in soft tissue sarcoma (Sarcoma in the Phase table), ovarian, breast, endometrial, prostate and non-small-cell lung cancers. PharmaMar indicated in January 2004 that it intends to launch trabectedin in one of these indications in 2006. PharmaMar raised funds from a round of financing in June 2005 that will be used to fund further clinical trials of its anticancer products, including trabectedin. The US FDA granted trabectedin orphan drug status for ovarian cancer in April 2005. Trabectedin also received orphan drug status from the European Commission for the treatment of ovarian cancer in October 2003. This followed a positive opinion by the Committee for Orphan Medicinal Products (COMP) of the EMEA. Trabectedin has undergone a phase II study for the second- or third-line treatment of ovarian cancer in Europe (England and Belgium), the US and Canada. The trial was initiated in October 2002 and evaluated a weekly schedule of trabectedin (0.58 mg/m(2)) via IV infusion for 3 weeks followed by a week of rest. Final results from this study have been presented. A separate phase II trial evaluating the antitumour activity of trabectedin as a second-line therapy in advanced ovarian cancer was conducted by researchers at the Southern Europe New Drugs Organization (SENDO) in Milan, Italy. PharmaMar and Johnson & Johnson are conducting a pivotal (STS-201) trial to compare a weekly and daily dosing regimen of trabectedin among patients with advanced or metastatic soft tissue sarcoma who are unresponsive to standard chemotherapy of doxorubicin and ifosfamide. The randomised, multicentre, open-label trial has completed enrolment of 270 patients during the second quarter of 2005. Positive data from the STS-201 trial have been announced. An independent data monitoring committee has found that interim data supports a positive trend in time to disease progression favouring patients receiving the daily dosing regimen. Consequently, all patients have been offered the option of switching to the daily regimen. Final results from the STS-201 trial will form the basis of MAA re-submission with European regulatory authorities. PharmaMar has held a pre-submission meeting with the EMEA and has presented a formal letter of intent to file for approval of trabectedin for soft tissue sarcoma. Previously, PharmaMar first filed for EU registration of trabectedin for treatment of advanced soft tissue sarcoma in November 2001, which was accepted for review by the EMEA and Swiss Health Authorities. However, the CPMP confirmed its recommendation not to grant trabectedin marketing authorisation in November 2003 following PharmaMar's appeal against the CPMP's negative opinion first announced in July 2003; the opinion was adopted by a majority vote rather than by consensus. Trabectedin was granted orphan drug status in Europe for recurrent soft tissue sarcoma in 2001. It was also granted orphan drug status by the FDA for the same indication in October 2004. Phase I studies are being conducted to evaluate trabectedin in combination with doxorubicin and liposomal doxorubicin for the treatment of soft tissue sarcoma. PharmaMar is also conducting a phase I study of sequential paclitaxel followed by trabectedin in patients with soft tissue sarcoma. At additional dose levels, patients with other tumour types will be enrolled to assess the antitumour activity of the combination. The US NCI has approved and is partially funding a phase I clinical programme to determine the feasibility of using trabectedin to treat children with soft tissue sarcoma and bone sarcoma who are resistant to conventional therapies. PharmaMar has reported that trabectedin can be safely administered to children at doses up to 1100mg given as a 3-hour infusion, and that this dose will be used in further paediatric studies. Trabectedin has completed phase II studies for small round cell sarcoma and rhabdomyosarcoma, which are aggressive tumours occurring predominantly in children. A phase II study evaluating two dosing schedules of trabectedin has been conducted in patients with leiomyosarcomas or liposarcomas refractory to standard doxorubicin + ifosfamide chemotherapy. The study was conducted in Australia, Canada, Russia and the US.

Animals↗

Six Sigma: not for the faint of heart.

Six Sigma is an excellent quality and performance improvement tool. Like any tool, the results of using it are highly dependent on whether you use it with competence and on the right problem. This article will help you decide if your problem is well-suited for a Six Sigma approach and will suggest the optimum approach for planning and implementing Six Sigma methodology. Performance improvement methods can be grouped into two broad categories, based on the problem to be addressed. When the problem is relatively minor and localized, "evolutionary" methods may be suitable (e.g., quality circles, problem-solving staff meetings, continuous quality improvement [CQI], total quality management [TQM]). These tools work best when modest incremental improvements are sought, when major process redesign is not thought to be necessary, and when the avoidance of workplace disruption is desired. Reengineering and Six Sigma are the best-known examples of the "revolutionary" performance improvement methods. These methods should be used when major (drastic, do or die, etc.) improvements are needed. Problems that cross departmental boundaries need these methods. When a process is so dysfunctional that you feel like you need to tear up the standard operating procedure (SOP) and start all over again, you need a revolutionary method. A Six Sigma project requires a major expenditure of money and employee time, and a willingness to make some hard decisions about jobs, employee retention and relationships among stakeholders. An institution's culture should be considered as part of the decision about using Six Sigma. If the institution has a history of making data-driven decisions, or at least has displayed openness to operating in that manner, Six Sigma has a good chance of success. A radiology-driven Six Sigma project should not be undertaken until a comprehensive written description of the scope of the project is approved by the radiology department leadership team and by the appropriate higher-level institutional leaders. This document should address the specific outcomes desired, the resources available, a rough tentative timeline, and any political constraints imposed on the project (e.g., inviolate HR policies, compatibility with enterprise strategic goals). The document should be comprehensive enough and explicit enough to be useful as a major component of the bid package for hiring a consultant or for writing the job description for the hiring of an in-house expert. A full-time project manager should be designated if an in-house expert is not hired. This person should be a senior leader in the department, but not the department director. Leading a Six Sigma project is a full-time job in itself and cannot be performed as an additional duty. Although it may be tempting to appoint a senior staff technologist or nurse, keep in mind that the project manager must have sufficient authority to expect cooperation from departmental supervisors without resorting to frequent appeals to the department director. Contact the institution's CIO and ask that a knowledgeable person on the IT staff be appointed to serve as the IT liaison for the project. This person should have in-depth familiarity with the HIS and the ways that it interfaces with the RIS (if the RIS is not a module within the HIS). Most importantly, this liaison must understand the exact data definitions and the origins of the data that are passed between the HIS and the RIS. The steering committee should consist of at least one physician and one department-level administrator from outside of the radiology department. From within the radiology department, there should be at least one radiologist and one senior modality manager (whose modality is not the primary focus), the project manager, and the manager of a radiology component that is a focus of the project (e.g., the film library manager). The consultant should be an ex officio member without vote. The steering committee should be small enough to be manageable, yet large enough to provide insight from both the radiology department and the rest of the institution. Because of the size of the steering committee and the difficulty of bringing so many people together for meetings, the day-to-day governance of the project will be provided by an informal "operations committee." When we consider "change" in the context of a Six Sigma project, we talk about a wide variety of topics, but they can be summarized usefully as dealing with processes, policies, physical plant and equipment, personnel, and politics (or culture). The first three of these lend themselves to quantitative analysis, or at least rigorously qualitative analysis. The final two, however, are subjective, ill-defined or not readily acknowledged, and fraught with potentially major challenges when it becomes necessary to implement changes in the first three. The Six Sigma process, as taught by GE, consists of five phases summarized by the acronym DMAIC: Define, Measure, Analyze, Improve and Control. This article deals mostly with the time period from first consideration of a possible Six Sigma project through the early part of the Define phase. It also discusses pitfalls that must be considered anytime throughout a project, from first thoughts of conducting a project until recommended changes become ingrained in the department's operations. Six Sigma compares baseline or historical data to data obtained after implementation of Six Sigma-driven changes in order to determine if desired changes in performance have been achieved. When historical data are not available, the Six Sigma team must collect baseline data as one of their earliest tasks. A Six Sigma project can easily last 18 to 24 months or longer. We must be sure that the data we collect during Month 18 are collected identically to the data we collected at baseline. A major performance improvement project is likely to require 12 to 24 months or longer. Upper management initially may be reluctant to appoint the "cream of the crop" to the project teams. Success is predicated on having the most knowledgeable personnel involved in the project. Without them, the chances of success are reduced. A Six Sigma project's length always exceeds the attention span of the vast majority of its participants. The department director and project manager must anticipate this and devote special efforts to maintaining motivation and momentum after the initial flurry of activity. The complexity of a Six Sigma project will be greatly increased, and all of the pitfalls discussed here will be exacerbated, if your facility has multiple sites. At the simplest, the multiple sites will introduce complications in getting personnel to come to project meetings. The complications will escalate if the sites are under different management, such as a confederated health system. The project manager and the consultant will expend additional time and effort dealing with these issues, which likely will lengthen the project unavoidably. The project manager must spend time with the department's external customers who have significant stakes in the project. At a minimum, this should include relatively formal meetings with other department directors or subordinate managers and key physician and nurse leaders, and attendance at their managerial or staff meetings (you may need to ask to be invited). Although paper or e-mail surveys can be helpful, only sustained personal contact with a stakeholder will truly allow you to understand how they interact with radiology and what their concerns are. As with daily operational management, a performance improvement project requires attention to policies, procedures, processes, physical plant and infrastructure, personnel, and perhaps most importantly, to politics.

Efficiency, Organizational↗

Influenza virus vaccine live intranasal--MedImmune vaccines: CAIV-T, influenza vaccine live intranasal.

MedImmune Vaccines (formerly Aviron) has developed a cold-adapted live influenza virus vaccine [FluMist] that can be administered by nasal spray. FluMist is the first live virus influenza vaccine and also the first nasally administered vaccine to be marketed in the US. The vaccine will be formulated to contain live attenuated (att) influenza virus reassortants of the strains recommended by the US Public Health Service for each 'flu season. The vaccine is termed cold-adapted (ca) because the virus has been adapted to replicate efficiently at 25 degrees C in the nasal passages, which are below normal body temperature. The strains used in the seasonal vaccine will also be made temperature sensitive (ts) so that their replication is restricted at 37 degrees C (Type B strains) and 39 degrees C (Type A strains). The combined effect of the antigenic properties and the att, ca and ts phenotypes of the influenza strains contained in the vaccine enables the viruses to replicate in the nasopharynx to produce protective immunity. The original formulation of FluMist requires freezer storage throughout distribution. Because many international markets do not have distribution channels well suited to the sale of frozen vaccines, Wyeth and MedImmune are collaborating to develop a second generation, refrigerator-stable, liquid trivalent cold-adapted influenza vaccine (CAIV-T), which is in phase III trials. Initially, the frozen formulation will only be available in the US. For the 2003-2004 season, FluMist will contain A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2) (A/Moscow/10/99-like) and B/Hong Kong/330/2001. Aviron was acquired by MedImmune on 15 January 2002. Aviron is now a wholly-owned subsidiary of MedImmune and is called MedImmune Vaccines. Aviron acquired FluMist in March 1995 through a Co-operative Research and Development Agreement (CRADA) with the US NIAID, and a licensing agreement with the University of Michigan, Ann Arbor, USA. In June 2000, the CRADA was extended through to June 2003. Aviron holds exclusive worldwide rights to the vaccine except for Japan, where Kaketsuken Pharmaceuticals (also known as Chemo-Sero-Therapeutic Research Institute) is the licensee. Aviron signed a development and licensing agreement with Sang-A in Korea, which was to manufacture and market FluMist in South Korea. However, in 2000, Aviron terminated all rights and licences to Sang-A relating to FluMist. Sang-A responded by filing a suit against Aviron in August 2000, for breach of contract and unfair and deceptive business practices. Aviron filed a counter claim denying the allegations in late Sept 2001. In 1999, Aviron entered into an agreement with Wyeth-Lederle Vaccines for worldwide collaboration in the marketing of FluMist. Under the $US400 million agreement, Aviron granted Wyeth-Lederle Vaccines exclusive worldwide rights to market FluMist. Wyeth-Lederle Vaccines and Aviron (now Med-Immune Vaccines) will co-promote FluMist in the US, while Wyeth-Lederle Vaccines will have the exclusive right to market the product ex-US. Wyeth will hold marketing rights for up to 11 years. The collaboration excludes Korea, Australia, New Zealand and certain South Pacific countries. The companies will collaborate on the regulatory, clinical and marketing programmes for FluMist and both will manufacture liquid FluMist. MedImmune Vaccines is to receive an average of 40% of revenues from FluMist; the percentage will be higher in the US and lower in other markets. Aviron received a $US15 million upfront payment upon initiation of the agreement. In December 2000, Aviron received a $US15.5 million milestone payment from American Home Products (now Wyeth) after the US FDA accepted the BLA for FluMist. MedImmune Vaccines will receive a $US20 million milestone payment upon US FDA approval. Aviron also received an additional $US20 million in milestone payments for expaory body recommendations. MedImmune Vaccines is entitled to receive a $US10 million payment for submitting a licence application in Europe, a $US27.5 million payment for approval of a refrigerator-stable liquid formulation of FluMist and as much as $US50 million for licensing of FluMist internationally. In July 2003 MedImmune announced that it had received approximately $US28 million in milestone payments during Q2 of 2003 for the approval of FluMist. CSL Ltd of Australia will collaborate on the development, sale and distribution of MedImmune Vaccine's vaccine in Australia, New Zealand and certain countries in the South Pacific. MedImmune is to acquire vaccine research programmes in respiratory syncytial virus and cytomegalovirus from MedImmune Vaccines. The company's primary interest is in FluMist. In May 2002, MedImmune licensed exclusive rights to Crucell's proprietary human cell line PER.C6 for use in its influenza vaccine programmes. On 11 March 2002, American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth-Lederle to Wyeth. Wyeth's vaccines division is called Wyeth Vaccines. On 29 September 2000, Aviron announced that it had been awarded a $US2.7 million Challenge Grant from NIAID for development of vaccines against pandemic strains of influenza based on FluMist intranasal technology. The cold-adapted live influenza vaccine has been widely evaluated in the US and Japan since 1975 in clinical trials involving several thousand people. Aviron completed phase II clinical trials in adults in the US and phase III trials in US children aged 15-71 months. Additional phase III trials in adults and the elderly are ongoing. Aviron also commenced phase III trials to test the safety of its intranasal live vaccine in children with moderate to severe asthma. The vaccine is delivered using the AccuSpray nasal delivery system by Becton Dickinson, which will supply the system for FluMist through the 2001-2002 influenza season under an agreement with Aviron made in August 1998. On 7 March 2000, Aviron announced that Wyeth-Lederle Vaccines (now Wyeth Vaccines) had begun a phase II bridging study with a refrigerator-stable liquid formulation of FluMist in the Southern Hemisphere. The randomised single-blind trial is being conducted together with Aviron (now MedImmune Vaccines) and is intended to demonstrate clinical equivalence between frozen and liquid FluMist. At the time of the announcement, more than 500 children aged 1-3 years had been enrolled to receive either frozen or liquid FluMist. The final study population is approximately 1300. If clinical equivalence of the two forms of FluMist is demonstrated in this study, MedImmune Vaccines will be able to use data from trials of frozen FluMist in licence applications for international markets. Aviron submitted a Biologics Licence Application (BLA) to the US FDA in July 1998. The FDA rejected this application on the grounds of a lack of data on manufacturing, validation and stability. In June 1999, Aviron announced that it had completed a bridging study on FluMist designed to provide some of the manufacturing data required by the US FDA on FluMist prepared at one of two manufacturing sites. Preliminary analysis indicated that the results had met the company's objectives. The primary endpoint of the study was to demonstrate that the batch of FluMist blended and filled at Packaging Coordinators, Inc. in Philadelphia had similar immunogenicity for all three 1997-98 influenza strains as the vaccine used in earlier clinical trials, which was manufactured by Medeva Pharma (now Evans Vaccines, a subsidiary of PowderJect Pharmaceuticals) in England. The secondary endpoint was to show that these lots of FluMist had similar safety and tolerability profiles. Aviron then submitted a BLA in October 2000. However, in late July 2001, an FDA advisory committee declined to recommend approval of the vaccine, citing concerns with safety. Aviron subsequently received a Complete Response Letter from the FDA requesting additional clinical and manufacturing data. Aviron stated that it should be able to provide these data without conducting further clinical trials. In January 2002, Aviron submitted additional clinical and manufacturing data on FluMist to the US FDA. MedImmune received a second Complete Response Letter from the US FDA on 10 July 2002, requesting clarification and additional data relating to previously submitted information. One of the most significant issues raised by the US FDA was the exacerbated rate of asthma and wheezing in 18-35-month-old patients using FluMist. MedImmune is considering two options to address this issue; to either exclude patients with asthma and wheezing from the label, or to exclude 18- to 30-month-old patients from the proposed indication. On 26 August 2002, MedImmune reported that it had completed the submission of information requested by the US FDA for FluMist. On 17 December 2002, the US FDA's Vaccination and Related Biologicals Products Advisory Committee (VRBPAC) recommended that the FDA approve FluMist to prevent influenza in healthy children, adolescents and adults (ages 5-49 years). Even though the VRBPAC voted in favour of the product's safety in the 50- to 64-year age group, they believed that the data set on efficacy for this age group was insufficient. The committee has also recommended that head-to-head studies should be conducted comparing FluMist to the marketed trivalent inactivated vaccine. Additional clinical trials suggested by the VRBPAC were shedding studies to more clearly define the probability of transmitting the influenza vaccine virus to a high-risk patient and annual revaccination studies. On 30 January 2003, MedImmune announced that it had received a Complete Response Letter from the US FDA requesting clarification and additional information relating to data previously submitted. No additional clinical trials were requested. The company responded to the five questions contained in the letter on 7 February 2003. (ABSTRACT TRUNCATED)

Administration, Intranasal↗