专家视点：丙型肝炎治疗的价格与成本

慢性丙型肝炎病毒(HCV)感染是肝病的一个主要病因，全球有1.8亿人罹患此病。HCV感染可以呈隐匿性或缓慢性进展，其并发症更是灾难性后果，故一直被描述为“病毒定时炸弹”。NS5B多聚酶核苷抑制剂sofosbuvir与聚乙二醇化干扰素α和利巴韦林联合治疗基因1或4型（持续12周）或与利巴韦林联合治疗基因2型（持续12周）或3型（持续24周）时持续性病毒学应答（SVR）率极好，副作用极少，证据确凿，故美国食品药品管理局（FDA）在2013年12月批准了该药。

不过，这股热情很快就被sofosbuvir单药治疗12周将近8万美元的高昂价格所浇灭。该费用超出经济发达国家中许多个人的平均承受能力，即使有医保和（或）患者协助项目，同时大大超出发展中国家的承受能力，而后者的HCV感染负担最重。

然而值得一提的是，这项具有高SVR率的治疗的费用可以在很大程度上抵消管理长期并发症所需的费用及慢性HCV感染的间接影响。而且，由于疗程与过去相比缩短，加上该治疗方案的副作用明显减少，因此其整体治疗费用可能与以第一代蛋白酶抑制剂为基础的方案相似，后者以往构成了基因1型的标准治疗。理想化研究表明基于sofosbuvir仿制药的方案在价格上大幅下降。


Christopher Moore医生

“费用为何非要如此之高？”这个问题将公众的常有顾虑与对药企策略感到困惑、怀疑并恼火的倡导者联系起来。 “价格”和“成本”这两个概念通常被混为一谈：前者是指购买者或是第三方愿意支付给销售商的金额；而后者是指商品或服务上市所花费的金额。制药行业肩负生产的高昂固定成本（研究和开发）及FDA对疗效和安全性的积极监管。价格是为了收回成本，并给予初始投资风险以回报。仿制药不包括这些极高的费用，所以价格较低。尽管如此，大家还是希望通过传统市场调控措施下调价格，如建立“非强制性的合作”。或许当竞争性产品在不久的将来上市时就能实现价格下降，或许通过与第三方支付方进行积极磋商也能够实现价格下调。Sofosbuvir的专利保护到2029年截止，因此除非有硬性许可，否则不大可能出现仿制药。这类干预或相关的威胁在许多国家都出现过，包括美国在内。但这种情况对于该药是不大可能发生的。

HCV市场每年的销售额估计在100亿美元以上，这是推动药物开发的巨大动机，由此产生了大量的处于各个研发阶段的药品供FDA审批。众多销售商品的竞争会把价格拼下来，也会促进质量的改进。在实行公费医疗制度的国家中就能看到这方面的一个极端的例子，其购买者惟一，因此对价格下调有很大的影响力。

硬性许可建立在良好道德意图的基础上，因为它抛开了盈利动机，但也催生了不稳定的经济环境，所以可能会扼杀今后的革新。从疫苗市场就能对此略窥一斑，在疫苗市场中，经济不稳定性导致销售商减少，无论是归因于自然缩减还是合并，最终的结果是革新、竞争和药物可及性下降。

药企不是道德代理人，与之相似，政府也应被视为道德公民能够实现一致性目标的工具。目前鼓励在医患中、购买团体中以及公共游说代理机构中进行积极的教育和合作，共同协商推动价格合理下调。

制药的利润是显而易见的，但正是利润动机才能第一时间把如此有效的药物以如此快的速度推向市场。对于从未上市的药品，患者既不能从中受益，也不会感觉缺憾。这种带有政治色彩且抛开综合经济参数的道德意图可能会对我们竭力保护的患者造成更大的长期危害。

我们希望价格和成本问题不会羁绊大量HCV患者接受现有的治疗及不久就会问世的其他高效的治疗方案。

作者介绍：Christopher Moore医生是移植肝病学的研究员，Steven Flamm医生是芝加哥西北大学医学院移植肝病学的主任、医学与外科学教授。Moore医生无利益冲突披露。Flamm医生是Vertex和吉利德公司的讲者；为Abbvie、Vertex及其他公司做研究及担任顾问，并为勃林格殷格翰公司开展科研。

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By: CHRISTOPHER MOORE, M.D., AND STEVEN FLAMM, M.D.

Chronic hepatitis C virus (HCV) infection is a major cause of liver disease affecting 180 million people globally. HCV infection, both silent and slow in its revelation, and devastating in its complications, has been described as a "viral time bomb." In December 2013, the Food and Drug Administration approved sofosbuvir, a nucleotide NS5B polymerase inhibitor, given compelling evidence that when taken with pegylated interferon-alfa and ribavirin for genotype 1 or 4 (for 12 weeks) or with ribavirin for genotype 2 (for 12 weeks) or 3 (for 24 weeks), sustained virologic response (SVR) rates are excellent, with very limited side effects.

The excitement has been tempered by the knowledge that sofosbuvir alone is priced at approximately $80,000 for a 12-week course. This cost is beyond the means of many individuals in countries with affluent economies, even with insurance and/or patient assistance programs, and vastly beyond those of developing countries – where HCV infection is most burdensome. It should be noted that the cost of therapy with high SVR rates may greatly offset the price required to manage the long-term complications and indirect effects of chronic HCV infection. And further, since the treatment is shorter than in the past and since the regimen has far fewer side effects, the overall cost of therapy may be similar to that of first-generation protease inhibitor–based regimens that constituted the standard of care for genotype 1 previously. With that said, idealized studies have shown that generic sofosbuvir–based regimens could be priced substantially lower.

The query "why must it cost so much?" articulates traditional concerns of the public and its advocates who feel confusion, cynicism, and anger at corporate strategies. As physicians and fellow citizens, armed with both Hippocratic and democratic principles, we immediately identify with these positions. Yet, we would also urge restraint in attempting traditional actions, such as government fiat, that would seek to arbitrarily lower price.

The concepts "price" and "cost" are commonly conflated: The former is the amount a buyer, or third party, is willing to pay the seller; the latter is the amount it takes to bring that good or service to market. The pharmaceutical industry is straddled with high fixed costs of production (research and development) and aggressive FDA regulatory control over efficacy and safety. Prices attempt to recapture cost and justify the risk of initial investment. Generic drug replication does not embody these extreme costs that are partially reflected in lower prices.

Nevertheless, it is hoped that price reduction through traditional market measures will be achieved, i.e., to create "cooperation without coercion." Perhaps price reduction will be achieved when competitive products reach the market in the near future. Perhaps price reduction will be achieved by aggressive negotiation of cost with third-party payers. Sofosbuvir retains patent protection until 2029; thus, generics are not readily possible outside of "compulsory licensure" – the ability of governments to violate patent law in periods of national necessity. Such intervention, or the threat of it, has occurred in many countries, including the United States. We believe it is unlikely to occur in this case.

The HCV market, estimated at greater than $10 billion annually in sales, provides a strong incentive for drug development – producing the multitude of agents in various stages of development for FDA approval. The competition of multiple sellers for buyers will drive down price and facilitate quality. An extreme example of this can be seen in countries practicing socialized medicine, which effectively have a single buyer, so there is greater leverage for price reduction.

Compulsory licensure, while based upon sound moral intentions, would stifle future innovation by removing profit incentive and creating an unstable economic atmosphere. It is informative to review the vaccine market, in which economic instability has led to fewer sellers, either from attrition or conglomeration. The ultimate consequence is decreased innovation, competition, and drug availability.

Corporations are not moral agents. Similarly so, government has no agency, but rather should be considered an instrument through which a moral citizenry can achieve agreed upon objectives. Aggressive education and collaboration amongst physicians and their patients, purchasing groups, and public lobbying agencies to collectively negotiate reasonable price reduction are encouraged – to realize the potential we have as buyers en masse.

Pharmaceutical profits may be conspicuous, but nevertheless, it is that very incentive of profit that brings such powerful drugs so quickly to the market in the first place. Patients can neither benefit from nor feel the loss of drugs that never make it to market. A morality of intention, absolved of comprehensive economic parameters, while psychologically enticing and proximally politically advantageous, would lead to greater long-term harm for the very patients we have vowed to protect.

We hope that price and cost issues will not prohibit large numbers of HCV-afflicted patients from receiving the current therapies and other highly efficacious regimens that will soon be forthcoming.

Dr. Christopher Moore is a fellow in transplant hepatology, and Dr. Steven Flamm is chief of transplantation hepatology and professor of medicine and surgery, at Northwestern University Feinberg School of Medicine, Chicago. Dr. Moore reported having no conflicts of interest. Dr. Flamm is a speaker for Vertex and Gilead; does research and consults for Abbvie, Vertex, and other companies; and does research for BoehringerIngelheim.