Glaxo’s catalyst for creativity
The tight security around Glaxo-SmithKline's Stevenage research centre in the UK may partly be designed to deter animal rights activists, but it also serves to keep the company's secrets away from the eyes of its competitors.
Behind the high fences, metal gates and security guards, the landscaped 1980s campus resembles the Pentagon enough to have been used as the backdrop for the Hollywood film Spy Game starring Robert Redford.
But while GSK is keen to protect its innovations from the scrutiny of its rivals, it is proud to boast of what it believes to be the catalyst for them. At a time when European policymakers are preoccupied with the “Lisbon agenda” of how to maintain the European Union as a centre of high-level research and development while there is a continuing “brain drain” to the US, Stevenage provides a glimmer of hope.
More important for GSK, the site represents its best attempt to respond to a challenge for the entire pharmaceutical sector: how to reverse the recent draining of the “pipeline” of prospective drugs under development, sustain future corporate revenues, and reduce costs estimated at more than $800m for each new medicine that makes it to market.
Jean-Pierre Garnier recalls his concern when he took over as chief executive of GSK, following its creation from the merger of Glaxo Wellcome and SmithKline Beecham in 2000, and began to study in detail the combined group's pipeline. “We had an empty cupboard,” he says, before resolving to make his company the most productive in the industry.
Like its peers, GSK had invested heavily in techniques such as fast throughput technology, which vastly accelerates the basic reactions from its chemical “library” against new disease targets. But, as Mr Garnier puts it: “A fool with a tool is still a fool.”
His response, developed in co-operation with Tachi Yamada, whom he appointed head of research and development, was inspired by a trip to the company's operations in Belgium, where Jean Stephenne had been running a productive vaccines development unit in Rixensart near Brussels, now called GSK Biologicals.
The unit, a semi-autonomous business with an entrepreneurial culture more typical of a small biotechnology company than a drug multinational, became their reference point for the creation in early 2001 of seven “centres of excellence for drug discovery” (CEDDs) in Europe and the US, of which Stevenage houses two.
“Size was getting inthe way,” says Mr Yamadaas he reflects on thenegative impact on innovation of past corporate mergers. “In the bureaucracy, traditional biotechnology expertise was forgotten. Very few companies believed that they were failing in the 1990s. Many are just now realising how bad it is.”
The heart of his strategy was the creation of “fully empowered, multi-disciplinary teams” of no more than 300 people the size of many of the successful biotech companies with which GSK and its rivals have signed alliances. “I only rigidly control the headcount,” he says. “300 is a human size where people can hold each other accountable.”
In Stevenage, Garth Rapeport, the “CEDD-head” who runs the respiratory and inflammation centre, firmly believes that the new approach is working. “We have the same site, staff, people, journals, competitors and largely the same chemical libraries as before, but with a sharp increase in candidate compounds,” he says.
In reality, he is also building on a strong tradition. Stevenage long housed a respiratory division which developed Ventolin, the asthma drug dispensed through the ubiquitous turquoise plastic spray. It has since developed a replacement, Advair, with a new-style spray.
However, Mr Rapeport argues that the CEDDs have made a big difference. The first has been the ability to stop and start research projects more quickly than in the past, saving substantial research costs. “Before, we could be stuck for years with a project that was not viable, because the visibility was not there. The layers of management between me, the leadership team and the bench scientists have been compressed.”
Now, he says, he can “clean out failure” much earlier in the research on humans. Preliminary Phase 2A trials cost up to ￡1.5m ($2.9m) each. By stopping before the next stage, known as 2B, when large numbers of patients are tested, he avoids costs twice as large again. “We can have a Go/No Go decision within six months. For many of our competitors, that takes two years.”
A second change has been tighter integration of chemistry and biology, creating an approach dubbed “medicinal chemistry”. Those in the two disciplines work together closely to identify “targets” for disease in the body, and compounds to treat them.
In the same way, the CEDD co-operates closely with other parts of GSK, most notably a few minutes' drive away in the nearby town of Ware, where the asthma inhaler devices are assembled and the drug inserted. That has led to early co-operation as specialists from both sites discuss how far ideas developed in the laboratory are practicable for large-scale manufacture.
A third element of the new structure is greater focus than before. “If we were not a CEDD, we would be competing with 30-40 disease areas for advanced aids such as imaging technology,” says Mr Rapeport. “Here we have platforms that are very respiratory-specific.”
That has been helped by the fact that each CEDD has its own finance director, helping provide guidance and planning for a budget at Stevenage of ￡80m a year. “That makes a huge difference. It feels like a small business rather than a 3,000-4,000 person drug discovery organisation.”
Tighter financial control means that much of the basic work in developing compounds is now outsourced. “It's not what you've got in this business, but how you use it and bolt it together,” says David Allen, the CEDD's head of medicinal chemistry. “We are focused on our core skill of respiratory chemistry.”
Climbing the central stairwell of the main chemistry building in Stevenage, he points to “nodes” on each floor where staff sit and are encouraged to sip free coffee while exchanging ideas. “Universities generate great scientists who work as individuals at the fume cupboard, and write their own papers. We need transferable skills where you share generously and steal shamelessly.”
A final factor with the CEDDs is performance-linked remuneration, which accounts for about 20 per cent of the scientists' pay. But, as in any company,Mr Rapeport concedes that devising individual targets for team members is difficult. And he stresses: “I really do believe people are incentivised mostly by discovering new drugs.”
At the very least, there does appear to be a connection at Stevenage and Ware to satisfied patients, and an awareness of the risk factors linked to respiratory diseases. Officially, just 1 per cent of the total workforce smokes, and they are supposed to go off campus.
For all the management modifications, the success of Stevenage and the other CEDDs remains to be proven. Mr Rapeport says that just 10 “new chemical entities” entered clinical development in the four years ahead of the GSK merger, while in the five years since to the end of this year there will be 34.
But whether most or any make it to market as the US regulator's demand this week that GSK halts tests on its experimental MS drug 699 shows is another question entirely. As Mr Garnier stresses: “We are not claiming victory yet.”
葛兰素的创新催化剂
葛兰素史克公司(Glaxo-SmithKline)位于英国斯蒂芬艾治(Stevenage)的研究中心安全措施严密，这可能部分是阻止动物权利保护者进入，但也是用来保护公司机密不被其竞争对手窥见。
这个80年代建成的院落景色优美，围以高栅栏和铁门，还有众多警卫守护，可与五角大楼(Pentagon)媲美，因而曾被用作罗伯特?雷德福(Robert Redford)主演的好莱坞电影《间谍游戏》(Spy Game)的背景。
但是，尽管葛兰素史克积极保护其创新不受竞争对手的窥探，可它还是自豪地夸耀这座研究中心，视其为创新催化剂。目前欧洲的政策制定者十分关注“里斯本议程”(Lisbon agenda)，该议程针对人才不断流失到美国的问题，提出该如何维持欧盟作为高水准研发中心的地位。在这种情形下，斯蒂芬艾治研究中心提供了一线希望。
行业挑战
对葛兰素史克来说，更重要的是，该研究中心所代表的是，公司为应对整个制药业所面临的挑战而采取的最佳努力。这一挑战是：如何扭转近来潜在药物开发“管道”枯竭的趋势、保持公司未来的收入，并减少新药的成本。每种新药上市的成本估计为8亿多美元。
葛兰素威康(Glaxo Wellcome)和史克必成(SmithKline Beecham)在2000年合并成立了葛兰素史克，之后让-皮埃尔?加尼耶(Jean-Pierre Garnier)出任公司首席执行官，并开始详细研究这个合并后集团的药物研发计划。他回忆起当时的担忧。“当时我们的橱柜是空的，”他说，随后他决心让公司成为业内最多产的企业。
和对手一样，葛兰素史克也曾对高通量技术等进行重大投资，这大大加快了“化合物库”针对新目标疾病的基本反应速度。但加尼耶先生表示：“拿着工具的傻瓜还是傻瓜。”
他的这种反应是由对公司比利时运营部门的一次参观而引发的，并在与山田多知(Tachi Yamada)的合作中发展起来。山田多知是他任命的研发主管。在比利时，吉恩?斯蒂芬尼(Jean Stephenne)一直负责位于布鲁塞尔附近Rixensart的一家成效显著的疫苗开发部门，该部门现被称为葛兰素史克生物制品有限公司(GSK Biologicals)。
创业文化
这个部门是一家半自治企业，拥有一种创业文化，这种文化一般是小型生物科技企业而非跨国制药企业的特征。2001年早些时候，欧洲和美国7个“药物开发卓越中心”(centres of excellence for drug discovery, CEDD)的创立就是以该部门为参考标准。而这7个中心中有两家位于斯蒂芬艾治。
“规模逐渐成为障碍，”山田先生反思过去企业合并对创新造成的负面影响时说，“在官僚体系中，传统的生物科技专业技术被遗忘了。在90年代，几乎没有哪家公司相信自己正在败落。许多公司现在才刚意识到情况有多糟糕。
他的战略核心是建立一些“拥有完全授权的跨领域团队”，团队人数不超过300人，与葛兰素史克及其对手结盟的许多成功生物科技公司就是这个规模。“我只是严格控制人数，”他说，“在300人的规模下，人们能够相互负责。”
在斯蒂芬艾治，“CEDD负责人”加思?雷普波特(Garth Rapeport)负责这个呼吸炎症中心。他深信这种新模式在起作用。“我们的场地、员工、人、记录和竞争者都和过去一样，化合物库也和过去基本相同，但备选化合物却已大幅增长，”他说。
实际上，他还在巩固一个强大的传统。斯蒂芬艾治研究中心过去长期拥有一个呼吸系统分部，该部门开发了哮喘治疗药喘乐宁(Ventolin)，用非常普通的青绿色塑料喷雾器喷入口中。后来，该部门开发了一种有新式喷雾器的代替品：Advair。
但雷普波特先生认为，CEDD产生了很大影响。首先是制药公司能以比过去更快的速度停止或展开研究项目，大大节省了研究成本。“从前，我们可能连续几年纠缠在一个不可行的项目中，因为看不清状况。我、领导团队和实验室科学家之间的管理层级已被压缩了。”
剔除败笔
他说，如今在对人进行的研究中，他可以早很多“剔除败笔”。初期阶段的2A实验每次花费高达150万英镑(合290万美元)。下一阶段称为2B，届时将对大量病人进行测试。通过在2B前停止研发，他又能节省两倍的成本。“我们可以在6个月内就做出继续/停止的决定。我们的许多竞争对手要花上两年。”
另一个变革是将化学和生物学更紧密地整合，创造了一种名为“药物化学”(medicinal chemistry)的方法。这两个学科的人员密切合作，以识别体内的“目标”疾病，以及治疗这些疾病的化合物。
同样，该呼吸炎症中心与葛兰素史克的其它部门密切合作，尤其是与韦尔(Ware)小镇上的部门合作，这个小镇距该中心只有几分钟车程，哮喘吸入器就是在那里组装并填药。两地的专家进行讨论，探讨实验室中产生的构想在多大程度上可应用于大规模制造，从而展开早期合作。
核心技能
新结构的第三个因素是研究领域比以前更集中。“如果我们不是一个CEDD，我们就得与30至40个疾病防治领域进行竞争，以获得成像技术等先进辅助手段，”雷普波特先生说，“我们在这里有专门针对呼吸疾病的平台。”
每个CEDD都有自己的财务总监，帮助提供指导，并规划斯蒂芬艾治8000万英镑的年度预算，这点也很有好处。“这产生了巨大的影响。就像是一家小企业，而不是一家有3000至4000人的药物开发机构。”
加强财务控制就意味着，开发化合物过程中的大量基础工作现在都外包了。“这不是你在该公司拥有什么的问题，而是你如何使用它、整合它的问题，”CEDD的药化学业务负责人戴维?艾伦(David Allen)说，“我们专注于自己在呼吸化学方面的核心技能。”
在斯蒂芬艾治中心的主化学研究建筑内，他一边攀登居中的楼梯，一边把每层楼的“节点”指给我们看。员工们坐在节点，公司鼓励他们在此一边免费啜咖啡，一边交换创意。“大学培养伟大的科学家，他们独自在烟橱边工作，写着自己的论文。我们需要可转移的技能，你可以大方地分享、堂而皇之地窃取。”
CEDD的最后一个因素是，与业绩挂钩的薪酬约占科学家收入的20%。但雷普波特先生承认，同任何公司一样，很难为团队成员设置个人目标。并且他强调说：“我真的相信，发明新药是激励人们的主要因素。”
至少，斯蒂芬艾治及韦尔小镇似乎与满意的患者有着关联，而且意识到了呼吸系统疾病的相关风险因素。公司的官方数据显示，员工中只有1%吸烟，而且他们要离开公司场地才能吸烟。
尽管进行了种种管理调整，但斯蒂芬艾治和其它CEDD的成功还有待证明。雷普波特先生表示，在葛兰素史克合并形成之前的4年内，两家公司只有10个“新化学物”（new chemical entities）进入临床开发阶段，而从合并后到今年年底的5年中，将有34个进入临床开发阶段。
但其中有多少能最终上市则是另一个问题。美国监管机构本周要求葛兰素史克停止对实验性MS（多发性硬化症）药物699进行测试，就说明了这一点。正如加尼耶先生所强调的：“我们还未宣布获胜。”
