FDA关于缬沙坦事件的声明 20180830

恨我不成钢

Statementfrom FDA Commissioner Scott Gottlieb, M.D., and Janet Woodcock, M.D., directorof the Center for Drug Evaluation and Research on FDA’s ongoing investigationinto valsartan impurities and recalls and an update on FDA’s current findings

FDA声明：FDA专员Scott Gottlieb博士、CDER主任Janet Woodcock博士对FDA持续调查缬沙坦杂质和召回的声明，以及FDA目前发现内容的更新

For Immediate Release  立即发布

August 30, 2018  2018年8月30日

Statement声明

Millions of Americans take medication daily to control theirblood pressure. We recently found that some generic versions of one medication,valsartan, contain an impurity that doesn’t meet FDA’s safety standards.Valsartan is an angiotensin II receptor blocker (ARB) that treats high blood pressure and heart failure. The FDA currently has a major operation underway to investigate and address this troubling finding. This investigation is led by a dedicated task force of experts focused solely on this important work. Their mandate is to oversee the investigation and track new developments and information coming in from valsartan manufacturers. This multidisciplinary team of chemists, toxicologists, medical doctors, pharmacists, investigators,communication specialists, and analytical lab staff coordinates across the FDA, and acts on the newest available information.

上百万美国人每天服药控制其血压。我们最近发现有些仿制药品，缬沙坦，含有一种杂质，这不符合FDA的安全标准。缬沙坦是一种血管紧张素II受体阻滞剂（ARB），它治疗高血压和尽力衰竭。FDA目前已开始调查和解决此问题。此调查是由专门的专家工作组领导，他们目前全力承担此重要工作。他们的任务是监管调查，追踪来自缬沙坦生产商的新进展和消息。此多学科工作组包括有化学家、毒理学家、药学医生、药师、调查员、沟通专家以及分析实验室员工，他们在整个FDA内部协作，并对最新消息采取行动。

As our investigation continues to identify the root cause of this impurity, we want to take the opportunity to describe to the public what we are doing to find the cause of the impurity, to prevent a recurrence of this episode and to protect patients who need this medication.

由于我们的调查将继续找出此杂质的根本原因，我们想趁此机会向公众说明一下我们为发现杂质原因，为防止再次发生此类事件，以及为保护需要此药的患者而做的事情。

On June 19, a U.S. manufacturer of valsartan products,Prinston Pharmaceuticals Inc., contacted the FDA‘s Center for Drug Evaluationand Research (CDER) about its products containing valsartan active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceutical Co.(ZHP). Prinston informed CDER that they had stopped making valsartan products because ZHP had detected an impurity in the API – a chemical known as N-nitrosodimethylamine (NDMA). NDMA is a probable cancer-causing chemical found in trace amounts in water and some foods. However, the levels of NDMA in ZHP’s valsartan API – while still trace amounts – were unacceptable.

6月19日，一个美国缬沙坦生产商，普霖斯顿药业，联系了FDA的CDER办公室，说明了其含有由浙江华海药业（ZHP）所产缬沙坦API一事。普霖斯顿通知CDER说他们已经停止生产缬沙坦药品，因为ZHP在API中发现了一种杂质—化学名为N-二甲基亚硝胺（NDMA）。NDMA是一种可能导致癌症的化学物，在水中和一些食品中发现有痕量存在。但是，ZHP的缬沙坦API中的NDMA水平—虽然仍为痕量—是不可接受的。

Although the risk to patients taking the affected productsis extremely low, we take matters of pharmaceutical quality very seriously. We took immediate steps to address these findings.

尽管患者服用受影响药品的风险非常之低，但我们非常严肃地对待药品质量事件。我们立即采取了行动应对此问题。

Shortly after initiating our investigation, we learned that a foreign regulator was also reviewing medications containing valsartan API manufactured by ZHP and considering a recall. We have closely coordinated with the European Medicines Agency, European Directorate for the Quality of Medicines, Regulatory Operations and Regions Branch and Therapeutic Products Directorate of Health Canada, and the Pharmaceuticals and Medical Devices Agency in Japan since that time, sharing information about our investigation with them and other regulatory bodies and learning about their findings.

在启动我们的调查之后不久，我们知悉一家国外药监机构亦正在审评含有ZHP生产的缬沙坦API并考虑召回。我们当时与EMA、EDQM、加合大药监和日本PDMA协作甚为紧密，与其它药监机构共享了有我们的调查信息，并且获得他们的发现信息。

We recognized that we had to find answers to several important questions: How many U.S. valsartan products are affected? Where did the impurity come from? What are the potential health consequences of the impurity? How many patients are affected? How long have patients been exposed to NDMA? How do we ensure that patients and providers are informed so that health care is minimally disrupted? How do we prevent drug shortages? And could similar drugs also contain this impurity?

我们认为我们已经找到几个重要问题的答案：有多少美国缬沙坦药品受到影响？杂质从何而来？该杂质的潜在健康后果如何？有多少患者受到影响？患者暴露于NDMA有多少时间了？我们如何确保患者和药品提供者得到通报从而使得卫生保健中断最小？我们如何防止药品短缺？是否有类似药品亦含有此杂质？

Our first priority was to inform patients and health care providers. To do this, we had to verify the information about ZHP’s API to understand the risk to U.S. patients and the scope of APIs and products potentially affected by this impurity. We identified four manufacturers using valsartan API from ZHP for the U.S. market. We contacted them to ask if they knew about NDMA in their products and to recommend recalls of affected products. In addition to ZHP, we identified 13 other API manufacturers who supply more than 20 drug companies that make valsartan for the U.S. market. We made plans to determine if their products could also contain NDMA.

我们最优先的任务是通知患者和健康服务者。为此，我们核实了ZHP的API的信息以了解其对美国患者的风险，及可能受此杂质影响的API和药品的范围。我们联系了他们询问其是否知晓其药品中的NDMA事宜，并建议其召回受影响药品。除了ZHP以外，我们还发现有13个API生产商为20余个为美国市场生产缬沙坦的制剂公司供货。我们制订了计划以确定是否其药品亦可能含有NDMA。

By July 13, we had the information we needed to issue a press release stating that three companies had products containing NDMA and were voluntarily recalling them. One of the four manufacturers we initially identified required further investigation, but has since voluntarily recalled its products.

截止7月13日，我们已获得我们所需信息，签发了立即发布的声明，声明有3家公司的产品含有NDMA，并主动召回这些药品。4家生产商中有一家，我们起初认为需要进一步调查，但该公司主动召回了其产品。

However, we did not want patients taking valsartan to hear this news and abruptly stop their medications, possibly suffering serious medical issues, such as stroke. We needed to let patients know the specific products impacted by the recalls, so they could talk to their health careproviders and get prescriptions for products that had not been recalled. We began posting frequent updates to our website, listing first the valsartan products affected by the recall, followed by alist of the hundreds of products not affected at that time. We sharedthis information broadly across other communication channels known to reachconsumers and health care providers, such as social media, newswires and emaillistservs. Because this is a continuing investigation, more manufacturers may discover that their valsartan products contain NDMA and take steps tovoluntarily recall them. We encourage patients and prescribers to check these lists frequently for potential changes in the recall status of their medicine.We are continuing to update this information on a regular basis and update consumers over our social media platforms to ensure broad reach.

但是，我们并不想服用缬沙坦药品的患者听到此消息就立即停止用药，这有可能导致严重的医疗问题，如心脏病发。我们需要让患者知晓受召回影响的具体药品，如此患者即可与其医护人员讨论并获得不需召回的药品处方。我们开始频繁发布通告，对我们网页进行更新，首先列出了受召回影响的药品，然后是当时未受影响的上百药品。我们将此信息通过其它已知沟通渠道如社会媒体、新闻专线和电邮服务等广泛传播，以使其到达消费者和医护人员处。由于这是一个持续的调查，更多生产商可能会发现其缬沙坦药品含有NDMA，并采取措施主动召回。我们鼓励患者和处方人员检经常检查这些清单，以发现其药品召回状态的变化。我们会继续定期更新此信息，通过我们的社会媒体平台向消费者更新以确保全面传播。

CDER toxicologists and chemists evaluated the risk to the public. On July 27, we shared what our scientists were able to estimate was the theoretical risk that the impurity could pose to patients. We estimated that if 8,000 people took the highest valsartan dose (320 mg) from NDMA-affected medicines daily for four years (the amount of time we believed the affected products had been on the U.S. market), there may be one additional case of cancer over the lifetimes of these 8,000 people beyond the average cancer rate among Americans. This estimate represented the highest possible level of NDMA exposure. It was a measure of the risk under the most extreme circumstances. Most patients who were exposed to the impurity through the useof valsartan received less exposure than this worst-case scenario.

CDER毒理学家和化学家评估了公众风险。7月27日，我们分享了科学家们所估计的该杂质对患者的理论风险。我们估计如果有8000人每日服用最高剂量受NDMA影响的缬沙坦药品（320mg），持续4年（此为我们认为受影响药品在美国销售的时间长度），在此8000人群中其生命周期患癌病例相比美国平均患癌率会增加一例。此估计代表的是可能的最高水平的NDMA暴露情况。它是对最极端情形下风险的测量。大多数通过服用缬沙坦而暴露于此杂质的患者受到的暴露低于此最差情形。

In St. Louis, the FDA maintains the most advanced pharmaceutical laboratory of any regulatory agency in the world. As soon as we were aware of the NDMA impurity in certain valsartan drugs, we began collecting samples of all valsartan API and products marketed in the U.S. At the sametime, our scientists began developing a test to detect and quantify NDMA invalsartan API. NDMA’s properties make it difficult to find. To determine if valsartan products do contain this impurity, CDER’s scientists have now developed the gas chromatography-mass spectrometry (GC/MS) headspace testing method. We posted this method to the web to help manufacturers and regulators detect NDMA in valsartan API and tablets.

在圣路易斯，FDA有着世界上最先进的药监机构药物实验室。一旦我们知晓在特定缬沙坦药品中含有NDMA杂质，我们即会开始采集所有在美国销售的缬沙坦API和制剂的样品。同时，我们的科学家会开发分析方法检出并定量缬沙坦API中的NDMA。NDMA的特性使得其难以发现。为确定缬沙坦药品是否含有此杂质，CDER的科学家们现已开发出了气相色谱-质谱（GC/MS）顶空方法。我们将此方法发布在官网帮助生产商和药监机构检出缬沙坦API和片剂中的NDMA。

Based on information provided regarding ZHP’s manufacturing processes, we believed (but did not have proof) that the impurity resulted fromchanges that ZHP made to the manufacturing process for its API. We needed to identify the root cause of the problem and evaluate ZHP’s explanation. After assessing information about ZHP’s manufacturing processes and the changes ZHP made over time, we identified how its processes could have led to the presence of NDMA in their API.

根据所提供的ZHP的生产工艺信息，我们相信（但并无证据证明）该杂质来源于ZHP对其API生产工艺的变更。我们需要发现问题的根本原因，评估ZHP的解释。在评估了关于ZHP生产工艺及其长时间内所做的变更信息之后，我们发现了为何其工艺可能导致其API中出现NDMA。

Specifically, a combination of conditions, which include certain chemicals, processing conditions and production steps, could lead to formation of the NDMA impurity. We believe that these risks are introduced through a specific sequence of steps in the manufacturing process, where certain chemical reactions are needed to form the active ingredient. Before we undertook this analysis, neither regulators nor industry fully understood how NDMA could form during this process. We are still not 100 percent sure that this is the root cause of the problem. Full understanding will require correlation of multiple test results from valsartan APIs made by different processes with the various process steps used by different manufacturers or atdifferent times. We need to determine how NDMA can be formed and why it is not separated from the API during purification.

具体来说，多个条件组合可能会导致形成NDMA杂质，其中包括有特定的化学物质、工艺条件和生产步骤。我们相信这些风险是通过生产工艺中特定的步骤顺序引入的，其中形成该API需要有特定化学反应。在我们进行此分析之前，药监和企业均不能全面了解NMDA在此工艺中是如何形成的。我们还不能百分百肯定这是问题的根本原因。全面了解需要对不同工艺生产的缬沙坦API的多个检测结果与不同生产商或在不同时间所用不同工艺步骤进行相关分析。我们需要确定NDMA要如何形成，以及为何未在精制过程中从API中分离出来。

Once we understand the way or ways that the NDMA impurity can occur as a by-product of the manufacturing process, we will make sure these conditions are evaluated in API synthetic processes so that, in the future, testing for this impurity would be required if there was a risk of NDMA formation.

一旦我们了解了NDMA杂质可能作为生产工艺副产物生成的一种或多种机制，我们就能确保在API合成工艺中对这些条件进行评估，在将来，如果有NDMA形成风险存在时就会要求对其进行检测。

NDMA is one chemical in a class called “genotoxic impurities”.These chemicals are of special concern to global regulators because, unlike most impurities in drugs, they have the potential to cause harm at very low levels. The FDA has worked with international regulators to create standards for mitigating the risk of such impurities. We have robust policies and procedures in place to guard against these risks.

NDMA是一种归类为“基因毒性杂质”的化合物。全球药监对此类化合物都会特别关注，因为与药品中其它大多数杂质不同，他们可能会在极低水平即导致伤害发生。FDA已与国家药监机构合作创建降低此类杂质风险的标准。我们有着强大的政策和程序防护此类风险。

The FDA will continue to improve its procedures for guarding against these impurity risks. We will use the information that we learn from our investigation into valsartan to strengthen our oversight.

FDA将持续改进其防护此类杂质风险的程序。我们将使用我们从我们的缬沙坦调查中获得的信息加强我们的监管。

In March 2018, the FDA issued a guidance for manufacturers that lays out risk assessements that manufacturers can use to evaluate the presence of genotoxic impurities. This is an internationally-harmonized guidance that both regulatorsand industry have agreed to. To implement the risk assessment for any genotoxic impurity, there has to be recognition that it can occur in the manufacture ofthe product. The guidance lays out the conditions under which these risks canoccur, and the steps that manufacturers should take to test for these potential impurities.

2018年3月，FDA发布了生产商可使用风险评估来评估其是否存在基因毒性杂质的指南。这是一份国际一致性指南，是受到药监和企业认可的。为实施对所有基因毒性杂质的风险评估，必须认识到在药品生产中可能产生该类杂质。该指南列出了此风险可能发生的情形，以及生产商应采取的检测这些潜在杂质的步骤。

Under the agency’s longstanding policies, manufacturers are required to test for impurities that may be introduced or develop during their manufacturing processes. We review that information in product applications,including requests to change the manufacturing process. We employ robust teams of organic chemists, as part of our newly established Office of Pharmaceutical Quality, to review applications and referenced information to look for steps –and manufacturing changes – where these risks could be introduced.

在FDA长期政策下，我们要求和平商检测在其生产过程中可能引入或产生的杂质。我们审核药品申报资料中的这些信息，包括生产工艺变更申请。我们有着严厉的有机化学家团队，作为我们新建立的药品质量办公室的一部分，审核申报资料和所引用的资料，以查找可能引入这些风险的步骤和生产变更。

The FDA also inspects manufacturing facilities across the world, and in routine current good manufacturing practices inspections, we can review a manufacturer’s records regarding impurity testing.  However, the review of records depends on appropriate tests to detect the impurity. Tests are selected based on assessments of what impurities may develop based on the manufacturing process. In other words, it needs to be recognized that the riskof an impurity can occur in order to know that it should be tested for.

FDA亦检查全球生产场所。在日常的CGMP检查中，我们可以审核生产商关于杂质检测的记录。但是，对记录的审核依赖于是否有适当的检测来发现该杂质。检测的选择是基于生产工艺会生成哪些杂质的评估的，换句话说，要先认识到杂质可能发生的风险，然后才知道要对其进行检测。

Recognizing these risks is based on a deep understanding ofthe chemistry involved in drug manufacturing, and the theoretical risk that animpurity could be a by-product of an essential step used in the manufacture of an active ingredient. When these impurities are identified, there are ways to re-engineer manufacturing processes to find pathways that don’t create these by-products. Because it was not anticipated that NDMA would occur at these levels in the manufacturing of the valsartan API, manufacturers would not have been testing for it. They would not have records that help identify this issueduring an inspection. So this particular risk would not have been identified on an inspection. As we develop a better understanding of the root cause of NDMA formation, and develop a way to detect NDMA in valsartan or other ARBs, we can ensure that appropriate testing is performed in the future.

对这些风险的认识是基于对药品生产中所涉及的化学知识的深入了解的，以及一种杂质可能会是API生产中所用基本步骤的副产物的理论风险。当识别出这些杂质时，有多种方法可以重新设计生产工艺，以发现不产生这些副产物的途径。由于并未预计到NDMA会在缬沙坦API生产过程中产生并达此种水平，生产商就不会对其进行检测。他们亦就不会有帮助在检查中发现此问题。因此，此特殊风险在现场检查中就无法发现。由于我们对NDMA形成的根本原因的有了更好了解，并建立了方法检出缬沙坦或其它ARB中的NDMA，我们可以确保在未来会执行适当的检测。

Based on our analyses of the manufacturing processes, we are now testing all the products in the ARB class to determine if they contain NDMA. In some cases, the steps in the synthesis of other ARBs can have similarities to the synthesis of valsartan. These tests will continue until we identify all products that may contain NDMA in the ARB class, and they are no longer available in the U.S. And our robust investigation continues, as do our efforts to mitigate these risks and prevent them from recurring.

根据我们对生产工艺的分析，我们现在正在检测ARB类别所有药品以确定其中是否含有NDMA。在有些案例中，其它ARB的合成步骤可能与缬沙坦合成类似。我们会继续此类检测直到我们找出可能含有NDMA的所有ARB类别药品，直至其不再在美国销售。我们的严格调查将继续尽力降低这些风险并防止其再次发生。

The FDA has also inspected ZHP in response to this problem and the agency may re-inspect ZHP and inspect other manufacturers of valsartan API in the future. The FDA is coordinating with companies to take swift action to remove any products found with unacceptable amounts of NDMA from the U.S.market.

作为对此问题的响应，FDA亦检查了ZHP，未来FDA可能会重新检查ZHP并检查其它缬沙坦API生产商。FDA正与公司协作采取快速措施从美国市场清除所有含有不可接受数量NDMA的药品。

The initial recall has expanded to now include five manufacturers and other companies who repackage those products under a different name. More products may need to be recalled. At the same time, the FDA is working to make certain that patients have access to the treatment that they need. Currently, more than half of all valsartan products on the market are being recalled. But prescribers can find a similar replacement product within the same class to substitute for patients who require this medication.

起始的召回现在已扩大至包括有5家生产商，以及其它对这些药品以其它名称进行分包的公司。可能会需要召回更多药品。同时，FDA正努力确保患者可获得其所需治疗。目前，正在召回的缬沙坦药品占市场量超过一半，但处方者可在同类药品中找到类似的替代药品提供给需要此药品的患者。

We are also working very closely with global regulatory agencies, including the European Medicines Agency. The task force the FDA formed exchanges information with regulatory counterparts around the world including inspection findings, laboratory test method and results, and our scientific assessment of the cause of this problem and its impact on patients.While not every manufacturing site produces drugs for all countries, we believe sharing this information is vital to advancing our ongoing investigation. Itenables us to address emerging issues quickly in a way that benefits U.S.patients. This includes monitoring actions other regulators are taking as partof their investigations. For example, international regulators have identified another API manufacturer, Zhejiang Tianyu Pharmaceutical Co., with NDMA in its valsartan API. But the FDA has confirmed that no valsartan products in the U.S.market use this API.

我们亦与全球各药监局紧密合作，包括EMA。FDA的工作组与全球药监伙伴订有信息交换机制，信息包括有检查缺陷、实验室检测方法和结果，以及我们对此问题原因的科学评估和其对患者的影响。由于并不是每个生产场所都为所有国家生产药品，我们相信共享这些信息对于促进我们持续调查是必要的，其中也包括其它药监正在采取作为其调查一部分的监测措施。例如，国际药监机构发现了另一个API生产商，浙江天宇药业，在其缬沙坦API中亦有NDMA。但FDA已确认美国销售的缬沙坦药品并未使用此API。

The FDA will continue to work closely with providers and patients to address health care needs.

FDA将持续与医护机构和患者紧密合作，解决其卫生工作所需。

The news of the recall caused a significant public response.Consumers were rightly concerned. CDER has a skilled group of pharmacists and nurses who manage a toll-free number (855-543-3784) and answer email inquiries (druginfo@fda.hhs.gov)from the public. Since the first news of a recall, the FDA has received more than 6,000 inquiries from patients, physicians, nurses, pharmacists and academicians. We take these inquiries very seriously, and we strive to answerall of them. The public wants to know how to get safe valsartan, what to tell their pharmacists, if they should stop taking their medications and how to calculate their risk for cancer if they have been taking affected valsartan for several years. It was these questions, in part, that prompted the FDA to conduct its analysis of the risk that NDMA posed.

召回新闻引发了强烈的公众反响。消费者对此非常关注。CDER有一个训练有素的药师和护士团队接听公众免费电话，回答电邮咨询。自从首个召回新闻发布以来，FDA已收到了来自患者、医生、护士、药师和学者的6000余次咨询。我们非常重视这些询问，我们努力对所有咨询做出回复。公众想要知道如何获得安全的缬沙坦，要怎么告诉他们的药师，他们是否应停止服药，以及如果他们已服用受影响缬沙坦数年，要如何计算其患癌风险。正是这些问题，部分促进了FDA对NDMA带来的风险进行分析。

As we develop a better understanding of the manufacturing process conditions that ZHP used that can cause the impurity, we will use that knowledge to inform assessments of product applications being submitted and currently reviewed by the FDA. We will disseminate that information to manufacturers of all drugs and to the scientific community and re-evaluate our existing guidance to manufacturers. In addition, the test method we developed for identifying NDMA helps us to prioritize assessments and inspections of manufacturing sites. The information we gather throughout this investigationwill give us a better understanding of the manufacturing processes and will strengthen our efforts to keep the U.S. drug supply safe for patients.

由于我们现在对ZHP所用可能导致杂质的生产工艺条件更为了解，我们将使用这些知识来评估正在提交的以及FDA正在审核的药品申报资料。我们会将这些信息传播给所有药品生产商和科学圈，并重新评估我们当前对生产商的指南。另外，我们开发的识别NDMA的检测方法将帮助我们优先评估和检查生产场所。我们通过此次调查收集的信息将让我们更好了解生产工艺，为患者加强我们保持美国药品供应安全的能力。

In addition to our ongoing investigation, we will continue to update our website, detailing lists of all recalled and non-recalled valsartan products as well as advice for patients and prescribers.We will also disclose our test results. This is a serious matter that is being managed closely by the FDA’s leadership. As described above,we have a robust effort underway to evaluate these risks, led by a team of some of our most experienced scientists and clinicians. As we continue to investigate this episode, and develop new information, we will update the public regularly. We are committed to identifying the root causes of this impurity being found invalsartan, and taking steps to reduce the risk that similar episodes occur in the future.

除了我们持续的调查外，我们将继续更新我们的官网，详细列出所有召回的和不召回的缬沙坦药品，以及为患者和处方人员提供的建议。我们还会发布我们的检测结果。这是一次严重事件，由FDA的领导密切管理。如上所述，由我们最有经验的科学家和临床专家团队领导，我们已不懈努力地评估这些风险。我们将持续调查此事，获取新的信息，我们将定期向公众更新。我们承诺找出缬沙坦中所发现此杂质的根本原因，并采取措施降低未来发生类似事件的风险。

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

FDA作为美国卫生福利部的机构，将通过确保安全有效保护公众健康，保护人兽用药、疫苗和其它人用生物药品以及医疗器械。FDA亦负责我们国家食品供应、化妆品、膳食补充剂、有电子辐射的产品的安全，以及管理烟草产品。

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