Treatment regulation
More than a year ago Maria Corina Roman was told she had less than 12 months to live. The 40-year-old surgeon had been living with cancer since 2001, when an invasive carcinoma or tumour was found on her left breast. Doctors had tried surgery, first removing her breast and then her lymph nodes. She also underwent radiotherapy and chemotherapy. Despite these efforts, a scan revealed multiple spine metastases secondary cancerous growths from her thorax to her cervix.
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“By January 2004 my whole situation was more critical, with pain, fatigue, weight loss and depression. I was also suspected for lung metastases and liver metastases,” she says from her home in Arhus, Denmark.
Mrs Roman stopped working and prepared to say goodbye to her two young children. “That was the point when I read in one of our medical magazines that the world's first gene therapy product would be approved in China.” She believes that chance discovery saved her life. Now she is back working as a surgeon and raising her children.
The cancer treatment she stumbled across was Gendicine, which fights tumours when injected into the body by introducing a healthy version of an important tumour-suppressing gene.
Gendicine is the only gene therapy in the world to have received regulatory approval, after it was authorised by China's State Food and Drug Administration. The drug was developed by Peng Zhaohui, a Chinese scientist who founded SiBiono, a private company, in 1998 after his return from the US, where he was a visiting professor at the University of California. China's decision to approve Gendicine signals a desire to move beyond making generic copies of proven pharmaceuticals to developing a new generation of biotechnology products.
This bold step, which follows the reorganisation in 2003 of the SFDA, founded in 1998, divides gene therapy researchers in the west. Their main concerns are potential lack of transparency in China's drug regulation system and potentially lower standards for clinical trials. These misgivings have been accentuated by commercial concerns about patent violations, particularly in the US.
Dr Peng points out that human genes cannot be patented. The crucial p53 gene that Gendicine uses for its therapy is thought to be at fault in more than half of tumours, and has been widely studied. The tricky bit is engineering a virus that can deliver the gene to the tumour safely. SiBiono holds a Chinese patent for this process and for the drug and has applied for international versions.
Dr Peng opened SiBiono's laboratories in Shenzhen with seed money from Beijing's science and technology fund. The company has since received about $40m in state aid and more than $60m in private investment from the domestic pharmaceutical industry. The company is using the funds to build a new facility with the capacity to produce 150m doses of Gendicine a year, equal to $581m to $968m in annual sales, with the help of New Brunswick Scientific, a US supplier of laboratory equipment.
The company is now looking for a large international partner to market the drug internationally. “We want a global biotechnology or pharmaceutical company as a partner,” says Dr Peng. Steve Jackson, a Cambridge university scientist supported by Cancer Research UK, welcomes the initiative: “It is very complementary to what is going on in the west. If China is successful it puts pressure on regulatory bodies, such as the US Food and Drug Administration, to take a more pragmatic and flexible approach to gene therapy.”
But Marshall Posner, a prominent researcher in Harvard's Head and Neck Oncology Programme, is sceptical. He is concerned by the limited clinical trial data published by SiBiono so far: “They have not yet released any data in an inter-nationally accessible, peer-reviewed journal that would allow objective analysis or confirmation of the statistics they have offered.”
Dr Peng says six years of trials have shown Gendicine to be safe and effective and, when combined with chemotherapy and radiotherapy, three times more successful than these therapies alone.
SiBiono says more data will be released in June when Chinese scientists attend the annual meeting of the American Society of Gene Therapists. But the trials and data are not up to US and European standards, counters Dr Posner. In fact, he is dismissive of China's entire biotechnology effort to date: “They just don't have people that know what they're doing.” Dr Posner's attitude highlights some of the barriers to co-operation between Chinese and American academics, in spite of growing interest from US gene therapy companies in outsourcing research or joint ventures.
Mark Kay, director of Stanford University's human gene therapy programme in California, agrees there is a “trust factor” with China that needs to be addressed. But he foresees huge rewards if partnerships can be made to work.
He is most excited at the prospect of researching gene therapies for neglected diseases, such as malaria and hepatitis, that kill millions. “For example, if you want to treat hepatitis, China has a huge hepatitis B patient population,” he says, which makes it easy to recruit candidates for large scale trials. Dr Kay adds that it is important that US researchers are not seen to be exploiting poor patients. The benefits for developing countries, he says, lie in developing gene therapies that require simple one-off applications. On Gendicine itself, Mr Kay is reluctant to make a judgment. “It is very difficult to say, especially if it is someone's last hope.” Dr Posner, however, thinks travelling to China to receive Gendicine is “foolhardy”.
He is concerned it might prompt patients to “defer real treatment”. “If it worked, we'd give it to patients, and we'd charge them,” says Dr Posner, who like many US researchers, receives financial support from several pharmaceutical and biotech companies. Mrs Roman was the first of more than 400 westerners to receive Gendicine. The cost of each dose was $387 in a course of one injection a week for four to eight weeks. Her cancer was so widespread that it required trying out intravenous injection rather than direct injection into the tumour. Mr Posner concedes: “If they have demonstrated they can give it intravenously, that would be a plus . . . intravenous makes more sense because it targets tumours at all sites, while intra-tumoural injection typically is useless in most cancers because some of the tumours may not be detected or accessible.”
Intravenous delivery of the p53 gene is also being pursued by Introgen, a US biotechnology company that is hoping to get approval in 2006 from the US FDA for a similar drug to Gendicine, called Advexin. Introgen's filings to the US Securities and Exchange Commission cite Gendicine as a potential threat to future profits, but both Dr Peng and Max Talbott, Introgen's head of worldwide regulatory and commercial development, characterise contact between the companies as “positive”.
Mr Talbott, a former FDA director, says the hope that gene therapy would provide a cure for cancer by fixing faulty genes has been replaced by a more realistic idea that cancer will be managed rather than cured.
It is still too early to tell if Mrs Roman has really made a miracle recovery.
Highs and lows are not uncommon for patients battling cancer, and Dr Peng has recommended she take another course of treatment.
“今又生”能否化解怀疑
一年多前，玛利亚?科丽娜?罗曼(Maria Corina Roman)被告知，她已活不到12个月。这位40岁的外科医生从2001年起就患上了癌症。2001年，她的左乳被发现有侵袭癌(肿瘤)。医生尝试为她动手术，首先切除了她的左乳，然后去除了淋巴腺。她还接受了放射治疗和化疗。尽管进行了这些努力，但扫描显示，从她的胸部到颈部还是出现了许多脊椎转移肿瘤（继发肿瘤）。
“到2004年1月，我的整个状况已经更加危急，出现疼痛，疲乏，体重下降，抑郁。医生还怀疑癌细胞已转移到了我的肺部和肝部，”她在丹麦奥胡斯的家中说。
罗曼太太停止了工作，并准备同她的两个小孩告别。“就在那个时候，我在一本医学杂志上读到，全球首个基因治疗产品将在中国获得批准。”她相信，是这个偶然的发现救了她的命。现在，她已经恢复当大夫，并抚养着她的孩子。
她偶然发现的这种抗癌产品是“今又生”(Gendicine)。这种药在注射进人体后，会带入一种健康的抑癌基因，抗击人体内的癌细胞。
“今又生”获得了中国国家食品药品监督管理局(SFDA)的批准，成为目前世界上唯一获得监管部门批准采用的基因治疗药物。这种药物是由中国科学家彭朝晖发明的。彭先生曾在加州大学担任客座教授。他从美国归来后，于1998年成立了私营企业赛百诺(SiBiono)。中国批准“今又生”的决定表明，中国渴望在仿制已得到验证的药物基础上，进一步开发新一代生物科技产品。
中国国家食品药品监管局于1998年创立，在2003年进行重组。该机构大胆批准“今又生”，在西方基因疗法研究人员中产生了分歧。他们主要担心，中国的药物监管体系可能缺乏透明度，而且临床试验的水平可能较低。商业方面有关专利侵权的担忧加重了上述疑虑，尤其是在美国。
“人类基因不能得到专利保护”
彭博士指出，不可能为人类基因申请专利。p53基因是“今又生”疗法的关键。据说半数以上的肿瘤都可归咎于这种基因的突变，因而它一直得到广泛的研究。难点在于设计一种病毒，能把这个基因安全地传递到肿瘤中。赛百诺持有该过程乃至该药的中国专利，并已在申请国际专利。
彭博士依靠中国政府科技基金提供的种子资金，在深圳建立了赛百诺的实验室。此后，这家公司得到约4000万美元的政府资助和国内制药业逾6000万美元的私人投资。公司正利用这些资金，在美国实验设备供应商New Brunswick Scientific的帮助下建立一座新工厂，具有1.5亿剂“今又生”的年产能力，年销售额可达5.81亿至9.68亿美元。
赛百诺正在寻找大型国际合作伙伴，在国际上推销这种药物。“我们想找一家全球性生物技术或制药公司作为合作伙伴，”彭博士表示。
得到英国癌病研究组织(Cancer Research UK)支持的剑桥大学科学家史蒂夫?杰克逊(Steve jackson)对这一计划表示欢迎：“这同西方进行的事有很大的互补性。如果中国取得成功，将对美国食品药物管理局(US Food and Drug Administration)等监管机构带来压力，迫使它们以更加务实和灵活的方式对待基因疗法。”
怀疑观点
但哈佛大学脑颈部肿瘤项目(Head and Neck Oncology Programme)著名研究员马歇尔?波斯纳(Marshall Posner)对此持怀疑看法。他对赛百诺迄今公布的有限临床试验数据感到疑虑：“他们还没有在一本全球发行、经同行评审的刊物上公布过任何数据。如果他们这么做，人们就能对他们提供的数据进行客观的分析或验证。”
彭博士表示，6年的临床试验已表明，“今又生”安全有效，而且当它与化疗和放疗结合使用时，成功率比单独使用其中一种疗法高3倍多。
赛百诺表示，6月份中国科学家将出席美国基因治疗协会(American Society of Gene Therapists)的年度大会，届时将发布更多数据。但波斯纳博士反驳说，他们的试验和数据达不到美国和欧洲标准。事实上，他看不起中国迄今在生物科技方面所做的全部努力：“他们的人都不知道自己在做什么。”波斯纳博士的态度突出显示了中美学术界进行合作所遭遇的障碍，尽管美国基因治疗公司对研究外包或设立合资企业的兴趣越来越大。
加州斯坦福大学人类基因治疗项目主管马克?凯(Mark Kay)承认，在与中国合作方面，需要解决一个“信任因素”。但他预计，如果成功开展伙伴关系，将带来巨大回报。
最令他感到兴奋的，是针对一些被忽视疾病的基因疗法的研究前景，例如疟疾和肝炎，这些疾病夺走了数百万人的生命。“比如，如果你想治疗肝炎，中国就有大量乙肝病人，”他说，因此很容易找到愿意参加大规模试验的人。
凯博士强调说，重要的是，美国研究人员不被视为在利用贫穷的病人。对发展中国家而言，这么做的好处在于，能开发只需一次给药的简单的基因疗法。
就“今又生”而言，凯先生不愿做出评价。“这很难说，当它是某些人最后的希望时尤其如此。”但波斯纳医生认为，去中国接受“今又生”治疗是“莽撞的”。
他担心这可能会使患者“延误真正的治疗”。“如果这种药有效，我们会给患者使用，并收取费用，”波斯纳博士说。像许多美国研究人员一样，他接受几家制药和生物科技公司的资助。
静脉给药
接受“今又生”治疗的西方人有400多个，罗曼夫人是其中的第一个。一个疗程为4到8周，每周注射一剂，每一剂的费用是387美元。她的癌细胞分布如此之广，因此需要试验静脉注射，而不是直接注射进肿瘤内。波斯纳先生承认：“如果这些药证明可用静脉注射给药，那就是个有利之处……静脉注射更有意义，因为它针对分布在各处的肿瘤，而对于多数癌症来说，肿瘤注射一般没有用，因为一些肿瘤可能没被查到，或注射不到。”
美国生物技术公司Introgen也在采用静脉注射方法将p53基因注入体内。该公司希望，它的一种药能在2006年获得美国食品药物管理局(FDA)的批准，该药名为Advexin，与“今又生”类似。在提交给美国证交会(SEC)的文件中，Introgen将“今又生”称为公司未来利润的一个潜在威胁，但彭博士和Introgen全球监管和商业开发负责人迈克斯?塔尔伯特(Max Talbott)都称两家公司间的联系是“积极的”。
塔尔伯特先生原任美国食品药物管理局负责人，他表示，人们本来希望，基因疗法能通过修复病变基因来治愈癌症，但这一希望已被一种更现实的想法所取代，即癌症将被控制，而不是治愈。
罗曼夫人是否真已奇迹般地康复，现在下结论还为时太早。
对于同癌症抗争的患者而言，病情时好时坏很常见，彭博士建议她再接受一个疗程的治疗。
