制药业苦于寻找新畅销药

很早以前，制药业就已将其人力资源、信息技术和市场营销的大部分工作外包出去。但是属于业务核心部分的研发工作基本未被触及。当其它部门的规模大幅缩减的同时，内部研发人员仍在一如既往地工作，潜心于他们的科学研究和研发数据，力求开发出下一种力普妥或百忧解(Prozac)。

这种情况开始有所改变。

在未来四年里，制药行业将有1300亿美元的专利产品到期，管理层再也不能依赖单一的药品(比如力普妥)来推动收入。相反地，他们正在努力增加药物品种，希望能以少于8亿多美元的成本来开发产品，这个数字通常被认为是将新药推向市场所需的代价。

―我们认识到，目前的商业模式产生的回报率比以前要低，‖毕马威费城制药行业实践主任兼咨询部门负责卫·布隆伯格（David Blumberg）说道。公司正在加紧进行小规模收购和许可证授权交易、增加研发工作的外包、以及立项开发所谓的‗孤儿药品‘- 为数量相对较少的病人提供帮助的产品。

据旧金山投资公司美国博乐公司（Burrill & Co.）的统计，2009年，生物科技行业融资558亿美元，创下了历史记录，比2008年增加了86%。许可证授权交易 – 制药公司出钱买下对另一家公司开发的某种复方的营销权 – 是上述增长的主要推动因素。

仅在过去的几个月里该行业就集中签署了好几项合作协议。12月，制药巨头辉瑞与以色列Protalix公司签署了一项新的药物开发协议，Protalix公司的药物是针对一种非常罕见的基因酶缺乏症 - 戈谢病的（Gaucher‘s disease）治疗药物。根据协议，辉瑞向Protalix公司首先支付6000万美元并获得其药物的全球许可权。这一消息引起了整个行业的关注，因为这意味着全球最大的制药商正在考虑的候选药物瞄准的是数千人的市场，而不象在以前―畅销药‖经营模式下，瞄准的是数百万人的市场。

今年1月，瑞士制药商罗氏集团（Roche）将其部分药物发现工作外包给比利时生物科技公司Galapagos。根据外包协议，Galapagos将获得5亿7300万美元用于发现技术并

研发出治疗慢性阻塞性肺部疾病（COPD）的药物。当时，Galapagos的首席执行官Onno van de Stolpe对投资者表示，他相信大型制药公司将会提供更多外包工作。―我们处在制药行业的‗甜区‘，在发现研究领域，我们可以为制药商提供[他们寻求的]东西，‖他说道。

秘密共享

业内分析人士指出，另外还有许多更为大胆的尝试，其中包括礼来公司（Eli Lilly）所做的决策，该公司决定由外部承包商来对前景看好的分子进行测试。在过去十年间，大型制造公司很多时候都是在让外部公司或高校科学家来进行临床试验及开展一些研究。但是，让他们在早期就进行分子筛选意味着与公司共享秘密—对于一贯谨慎的制药业而言，该策略非同寻常。

无独有偶，葛兰素史克公司（GlaxoSmithKline）决定，让规模较小的生物技术合作伙伴来完成其早期的开发工作，另外还效仿了生物技术风险投资的模式。葛兰素史克公司的科研人员必须向公司高层和外部行业专家提出他们的观点，以获得融资来实施新的研发项目。与此同时，瑞士制药商诺华公司（Novartis AG）也摈弃了旧的商业模式 - 即不再开发用于治疗拥有―大市场‖的疾病的药物，例如老年痴呆症或癌症，以便于增加发现能够有效治疗疾病的机会。

这些公司希望通过制订这些新的策略，重新将重点移到科学研究而非市场营销上，并由此再次研发出有效的药物。制药公司似乎是孤注一掷，但是他们也别无选择。―这一切都非同寻常，‖布伦伯格（Blumberg）指出，―当外包首先出现在所有行业中时，基本准则之一就是，公司不外包战略和核心业务……而现在这些人却在将研发的重要部分外包出去。‖

大型制药公司对研发外包进行的分析，应有别于外包给其它公司的其它职能，比如信息技术，布伦伯格补充道。―其中的风险不同，而且更大。‖在旧的研发模式下，单凭一个科研人员或科研小组就能完成从药物初始发现、临床试验到产品发布的一系列工作。这些员工想方设法使他们的想法附诸实现。而其弊端在于，他们可能无法及早放弃无用的想法。好的方面是，他们对工作充满激情而且非常敬业，比如说，他们知道数据中的一个错误会给公司造成数百

万美元的损失。至于外部研发人员，由于他们有着许多不同的客户，可能不会象前者那样认真，布伦伯格指出。

―必须对这些关系加以深思熟虑和有效管理以获得成功，‖他说道，―不能把事情一股脑地推到外包伙伴身上。必须建立正确的激励机制。如果只是激励他们按时完成工作，那么质量是否会受到影响？如果只是激励他们注意成本，那么时间和质量是否会受到影响？‖

新型组织模式

沃顿商学院管理学教授拉里·赫比尼亚克（Larry Hrebiniak）指出，事实证明，在创建新的合作关系时，文化差异和组织问题的困难程度与科学不相上下。―棘手的地方在于，你打交道的对象是一些受过良好教育的人士 - 科研人员都希望能独自工作 – 没有办法建立管理机制或者将创新成果商品化，以及订立规章制度，‖他说道，―你会遇上麻烦。外部合作伙伴可能会着手做自己的事，全然不顾你的组织的战略需要。你也许想让你的人员与外包人员合作，但是你必须给双方一定的自主权。‖

投资其它公司或与其它公司开展许可证授权交易，这些都需要一定的技巧，而制药公司在这方面可能还不太擅长，他补充道。例如，思科公司以其系统有效的收购方法而著称，其重点就是了解哪些技术可能会带来赢利。要想使这类风险投资取得成功，―必须注重尽职调查，‖赫比尼亚克说道，―必须选择合适的合作伙伴 – 适合进行收购或创立合资企业的可靠候选人。你必须具备吸收能力，即公司发现、了解及整合新技术的能力。‖有些制药公司证明他们非常精于此道：去年，罗氏公司实施了一项战略行动，公司收购旧金山生物科技公司 – 基因科技公司（Genentech）44%的股份，两家公司的合作取得丰硕成果，成功推出罗氏公司的三大畅销药物：抗癌药物阿瓦斯丁（Avastin）、赫赛汀（Herceptin）及美罗华（Rituxan）。

但是，总的来看，大型制药公司的―跟风‖现象过于严重，沃顿商学院管理学教授赛凯特·胡乔瑞（Saikat Chaudhuri）说道，他的研究重点是公司并购。―这些企业在资产组合管理方面做得不好。他们都在追求相同的东西，他们都很保守并且把[并购]赌注都押在[范围很小的]药物上面。‖

但是，大型制药公司目前别无选择，只能去尝试，赫比尼亚克说道。―行业内的竞争压力很大。‖在10%到20%的公司收入都用于研发的情况下，大型制药公司根本没有能力负担现在这样的巨大开支，他说道。小型公司也在积极寻求合作。由于全球金融危机，上市已经普遍不再是一种融资办法。―他们需要现金。他们在寻求帮助，这就是小型公司寻求现金和与大型制药公司进行合作的动机。‖

不确定的科学

对于大型制药公司而言，专利到期并不是唯一的主要问题。沃顿商学院医疗保健管理学教授帕特里夏·丹泽教授（Patricia Danzon）指出，由于许多原因，行业形势已经大不如上世纪九十年代和本世纪初期时的情况。早几十年前，那些用于治疗数百万人的疾病的许多药物为公司带来了丰厚盈利。例如，几乎所有步入中年的人都会有胆固醇高的问题 – 这也是用于治疗该疾病的力普妥等药物大受欢迎的原因之一。同样地，抑郁症被称作精神疾病中的―普通感冒‖，因此，百忧解、舍曲林（Zoloft）、度洛西汀（Cymbalta）及其它治疗药物拥有巨大的市场。

如今，用于治疗阿尔采莫氏病的药物需求量很大，但是人们对疾病本身却知之甚少。科学家们甚至不知道阿尔采莫氏病是一种疾病还是多种疾病，这给治疗药物的开发增加了难度。另一种常见疾病 – 癌症，也有可能不是一种而是多种疾病，使得抗癌药物无法成为畅销药物。紧随着万洛药等产品丑闻的出现之后 – 研究发现，Cox-2抑制剂会增加中风和心脏病的风险，此后默克公司（Merck & Co.）在2004年将该药物召回 – 美国公众对风险的容忍度越来越低，因此，美国食品和药物管理局每年只批准大约20种药物。

―现实就是，低处的果实已被摘走，市场上也有不少好的药物可以治疗我们知道的一些疾病，因此，新药物必须要优于现有的药物，‖丹泽说道。

沃顿商学院营销学教授戈莫汉·拉朱（Jagmohan S. Raju）指出，通过投资小公司或签定许可证授权协议来与之合作，大公司将有机会获得有着良好前景的先进技术。―如果你在一家创业公司投资了500万美元……大家在董事会上讨论前景看好的开发项目时，你可以比竞争对手先行一步，因为你对此非常了解，‖他说道。

丹尼尔·霍夫曼（Daniel Hoffman）是费城地区的医药顾问。他怀疑，这些被追捧的战略是否能产生收益。许多这类解决方案本身就有问题。追求―孤儿药品‖风靡一时，这是因为诺华公司发明的格列卫（Gleevec）药物，该药物最初只是用来治疗一种罕见的血癌，之后发现此药物还能治疗另外六种危及生命的疾病。现在，格列卫药物的年销售额约为37亿美元，一些业界高管希望能通过―依葫芦画瓢‖，使他们的―孤儿药品‖取得成功。但是这绝非易事。即便公司能够发现药物可用于治疗相对罕见的疾病，他们也要面临因药物成本问题而引起的政治反应，因为孤儿药物的研制成本是非常高昂的。

―这就是力普妥或帕域斯（Plavix）的创收方法吗？‖霍夫曼问道，―我对此表示怀疑。虽然药物化学的科学范式在诸如心血管药物等领域取得了巨大成功，但是，此类范式能否在未来创造可观收益仍是值得怀疑的。‖

以下是外文原文

Pharma Is at Pains to Replace Blockbusters: Has It Found the Cure?

The pharmaceutical industry long ago farmed out much of its human resources, information technology and marketing work. But the research and development (R&D) at the heart of the business remained largely untouched. While other departments shrank, in-house scientists continued as they always had, staring into their microscopes and poring over data in the hunt for the next Lipitor or Prozac.

That is beginning to change.

As the industry comes to grips with the expiration of about $130 billion in patented products over the next four years, its executives can no longer bank on a single drug like Lipitor to drive earnings. Instead, they are aiming to diversify their drug portfolios, hoping to develop products for far less than the $800 million-plus figure often cited as the price of bringing a new drug to market.

\"There's a recognition that current models have a lower rate of return than they used to,\" says David Blumberg, principal and advisory sector leader for KPMG's pharmaceutical industry practice in Philadelphia. Firms are stepping up the pace of smaller acquisitions and licensing deals, outsourcing more R&D work and creating programs to develop so-called \"orphan drugs,\" products that help relatively small numbers of patients.

The biotech industry raised a record $55.8 billion in 2009, an 86%increaseover 2008, according to San Francisco investment firm Burrill & Co. Licensing deals -- in which a pharma company pays money for the rights to market a certain compound developed by another firm -- drove much of that jump.

The last few months alone have seen a rush of partnership announcements. In December, Pfizer licensed the worldwide rights to a treatment for Gaucher's disease, a rare genetic enzyme deficiency, from Protalix Biotherapeutics, an Israeli biotech company, for around $60 million. The news caught the attention of the entire industry because it meant the world's largest drugmaker was considering drug candidates that might help just thousands of people at a time -- rather than the millions that were typically targeted under the old blockbuster model.

In January, Swiss drugmaker Roche outsourced some of its drug discovery work to Belgian biotech company Galapagos. Under the deal, Galapagos could get as much as $573 million for applying its discovery technology to identify drugs to fight chronic obstructive pulmonary disease (COPD). At the time, Galapagos CEO Onno van de Stolpe told investors that he was confident big pharmaceutical companies would send more work his way. \"We are really in a sweet spot for the pharmaceutical industry [in that] we are providing them exactly what [they are looking for] with regard to discovery research,\" he said.

Sharing Secrets

Among the more radical experiments, according to industry analysts, is Eli Lilly's decision to allow outside contractors to test the company's promising molecules. For much of the last decade, big drug firms have let outside companies or university scientists conduct clinical

trials and do some research. But letting them screen molecules at early stages means sharing company secrets -- a highly unusual strategy for the cautious pharmaceutical industry.

Lilly is not the only company making such moves. GlaxoSmithKline has decided to let its smaller biotech partners do more of its early-stage development work, and it has taken the additional step of mimicking the biotech-venture capital model. Glaxo scientists now must pitch their ideas to panels of company executives and outside industry experts to win funding for new projects. Meanwhile, Swiss drugmaker Novartis AG has jettisoned the old model of pursuing drugs that could fight \"big market\" diseases, such as Alzheimer's or cancer, in favor of ailments where the science is well understood, improving the chances of finding a treatment that works.

The hope in these new strategies is that by refocusing on the science, instead of on marketing, companies will once again start churning out effective drugs. It's a huge gamble, but pharma firms have little choice.\"All of this is very different, very unusual,\" Blumberg notes. \"When outsourcing first started popping up in all industries, one of the general maxims was that you don't outsource what's strategic, what's core to your very being.... These guys are outsourcing what look like significant aspects of research and development.\"

Large pharmaceutical companies will need to analyze outsourced R&D relationships

differently than they do other functions -- like information technology -- that other firms have taken on for them, Blumberg adds. \"There is a level of risk that feels different and bigger.\" In the old R&D model, a single scientist or small team may have taken a drug from initial discovery through clinical trials to product launch. Those employees are very invested in getting their idea to work. The downside is that they may not be able to let go of an idea that didn't work early enough. But the upside is that they are passionate and committed, and they understand, for example, that a mistake in data could cost the company millions. Outside researchers, who could have many different clients, may not care as much, Blumberg notes.

\"These relationships have to be carefully thought through and navigated to be successful,\" he says. \"You can't just dump everything on an outsourcing partner. You have to create the right

incentives. If they're just incented to get the job done on time, does quality suffer? If they are just incented on cost, do time and quality suffer?\"

New Organization Models

According to Wharton management professor Larry Hrebiniak, the cultural and organizational issues in creating new partnerships can prove almost as difficult as the science. \"What makes it difficult is that you're dealing with very educated people -- research scientists who want to be left alone -- and it's impossible to try to bureaucratize or commoditize innovation, to develop rules,\" he says. \"You can run into trouble. The outside partner may just start doing its own thing and not fit with your organization's strategic needs. You want to somehow have your people working with their people, but you need to give them all some autonomy.\"

Investing in or doing licensing deals with other companies also requires skills that

pharmaceutical firms may not have honed, he adds. Cisco, for example, has become famous for its disciplined approach to acquisitions, which focus on understanding which new technologies are likely to pay off. In order to have success in these ventures, \"you have to focus on due diligence,\" Hrebiniak says. \"You must find appropriate partners -- solid candidates for acquisition or joint ventures. You must have an absorptive capacity, which is the ability of a company to discover, understand and integrate new technologies that are out there.\" Some pharma firms have proven they can do this well: Last year, in a move that appeared strategically sound, Roche agreed to acquire 44% of San Francisco biotech Genentech, consummating a partnership between the two companies that had resulted in Roche's three top-selling drugs, the cancer medicines Avastin, Herceptin and Rituxan.

Generally speaking, however, big pharma companies seem to be playing \"follow the leader\" too much, says Wharton management professor Saikat Chaudhuri, whose work focuses on mergers and acquisitions. \"They don't do a good job of portfolio management. They tend to all go after the same things. They tend to be conservative and place their [M&A] bets on [a narrow range] of drugs.\"

But now big pharma has little choice but to try, Hrebiniak notes. \"Competitive pressures in the industry are quite high.\" Large drug companies simply can't afford to keep spending as much as they are now, when about 10 % to 20% of revenue goes to R&D, he says. Smaller companies are eager for partnerships, too, he adds. Because of the financial crisis, going public is generally not an option for raising capital. \"They need cash. They're looking for help, so there's a motivation on the small-firm side to seek cash and relationships with big pharma.\"

Unsure Science

For large pharma firms, patent expirations aren't the only major problem. The industry's fortunes have changed from the heady days of the 1990s and early 2000s for many reasons, says Patricia Danzon, a Wharton professor of health care management. Many of the drugs that swelled bottom lines in earlier decades treated diseases that affected millions of people. High cholesterol, for example, is almost a rite of passage for anyone entering middle-age -- one reason Lipitor and other drugs that fight it are immensely popular. Similarly, depression has been called the \"common cold\" of mental illnesses, so there was a huge market for Prozac, Zoloft, Cymbalta and other treatments.

Today, there is an overwhelming need for drugs to treat Alzheimer's disease, but the ailment itself is poorly understood. Scientists don't even know whether Alzheimer's is one disease or many, increasing the difficulty of developing treatments. Cancer, another common illness, also is likely not one disease but many, making a blockbuster cancer drug unlikely. In the wake of scandals over such products as Vioxx -- a Cox-2 inhibitor recalled by Merck & Co. in 2004 after studies indicated the drug was associated with increased risk of stroke and heart attack -- the American public also has grown less tolerant of risk, one reason that the U.S. Food and Drug Administration now approves only about 20 drugs yearly.

\"There is the reality that the low-hanging fruit has been picked, that there are a lot of good drugs already on the market to treat the diseases that we know how to treat, so something new has to be superior to the existing drugs,\" Danzon notes.

Partnering with a smaller company by investing in it or through a licensing agreement can give the larger firm a window into promising technology, says Wharton marketing professor Jagmohan S. Raju. \"If you're an investor with $5 million in an early-stage company and ... have someone sitting on the board, you could move earlier than your competitors on a promising development because you would know that much more about it,\" he says.

Daniel Hoffman, a pharmaceutical consultant in the Philadelphia area, is skeptical that any of the more popular strategies will generate the kinds of revenues the industry is about to lose. Many of these solutions come with their own problems, he says. Pursuing orphan drugs has become all the rage because Novartis took Gleevec, initially developed to treat a rare blood cancer, and found it treated six other life-threatening diseases. Gleevec now generates about $3.7 billion in yearly sales, and some industry executives hope to duplicate that kind of success with their orphan drugs. But that won't be easy. Even if companies can identify broader uses for treatments of relatively rare diseases, they may face political backlash over the drugs' costs, because orphan drugs are generally very expensive to develop and manufacture.

\"Is this a means of generating the kinds of revenue for which the sun is setting on a Lipitor or Plavix?\" Hoffman asks. \"I tend to doubt it. It's questionable whether the scientific paradigm of medicinal chemistry that has resulted in huge successes in areas like cardiovascular drugs can be as productive in the future.\"