专家呼吁广泛共享临床试验数据

《新英格兰医学杂志》10月21日在线发表的一篇文章呼吁，应尽可能广泛地共享临床试验数据，以推动科技创新和回答公共卫生方面的重要问题(N. Eng. J. Med. 2013 Oct. 21 [doi: 10.1056/NEJMhle1309073 ])。

主要作者、哈佛大学的Michelle M. Mello和来自药物研究与生产商、咨询公司的合作者指出：“问题不是是否，而是如何广泛共享这些数据。”至少应当在具备充分知识产权保护的所有国家共享所有关于已获准的处方药、器械和生物制剂的试验数据。应当建立专门的系统以确保负责任地使用这些数据，保护研究受试者的隐私，并且“公平对待所有合格的数据请求者和试验赞助者”，要求数据声称者和数据请求者按照同样严格的科学原则行事。

近15年来，人们对临床试验数据的需求日益增长，包括协议设计、结果总结以及原始输入数据等。一些医学期刊已开始根据请求披露更多数据。美国食品药品管理局(FDA)正接到越来越多的披露请求，而美国和欧洲的药企已承诺公开更多信息。从2014年3月开始，欧洲药品管理局(EMA)将要求披露一些原始数据、个案报告表和其他数据。

作者们设想了至少四种共享数据的可能模式。在完全开放获取的情况下，所有信息都可以免费下载。他们认为这是最危险的模式，因为这种模式将责任降至了最低。另一种模式：数据生成者将保留数据，但会答复非常具体的请求。第三种模式是由临床试验赞助者审阅数据请求并决定是否和如何发布数据。

在最后一种模式中，一个独立的评审委员会将决定是否应发布这些数据。委员会将在有限、须知的前提下，从赞助者那里收集数据并将其发给请求者。作者们认为，这一模式或许能最好地平衡各种竞争性需求。独立的委员会将能“确保数据生成者和使用者均担负责任，并允许试验赞助者说明延迟公开数据的理由”，还将有助于保护研究受试者和保证所有利益相关者受到同等的保护。

作者们指出，拓宽对患者水平数据的访问权将带来诸多好处，新的质询可能会暴露出产品瑕疵或试验设计缺陷，并且有可能回答与公共卫生相关但无法在原创性研究中探索的问题。最大的缺点是，受试者的个人隐私可能受到影响。披露数据的风险引出了一个关键问题，即如何确保受试者理解数据共享的潜在衍生。如果生产商认为数据会被竞争对手利用，那么强制性披露还可能妨碍对研发的投入。更广泛的数据共享还可能招致监管机构对批准令的二次审查。

世界医学会(WMA)在10月19日发表在《美国医学会杂志》上的最新版《赫尔辛基宣言》中关注了临床试验数据共享的问题(doi: 10.1001/jama.2013.281053)，3项一般原则涉及数据共享：

·第9项：参与医学研究的医生有责任保护生命、健康、尊严、诚信、自决权、隐私权，以及研究对象个人信息的保密性。保护研究对象的责任必须始终由医生或其他医疗专业人员承担，而永远不由研究对象承担，即使他们已经知情同意。

·第24项：必须采取所有可能的预防措施来保护研究对象的隐私权和个人信息的保密性。

·第32项：对于使用可辨认的个人资料或数据的医学研究，如对生物库或类似存储库中资料或数据的研究，医生必须找到收集、存储和/或重用的知情同意。有时可能会遇到无法获得知情同意的例外情况，此时只有在得到研究伦理委员会审议批准后才能开展研究。

本文的一些作者透露称为咨询公司服务，从而间接服务于多家生产商和学术医疗中心。这个工作组是通过哈佛大学多区域临床试验中心召集的，该中心从制药公司和非营利机构获得了资金。

随刊述评：数据共享将对研究产生助益

与制药业的担忧恰恰相反，我们认为，通过适当甄别获得临床试验数据的完全访问权限，将有利于以研究为基础的生物制药产业。我们预测，这将有助于增加药物开发的效率，提高成本效益，改善比较效益分析，并减少试验赞助商的重复努力(N. Eng. J. Med. 2013 Oct. 21 [doi: 10.1056/NEJMp1310771])。

一种允许共享患者水平数据并确保患者隐私权的托管发布环境，将为所有利益相关者创造一个公平竞争的平台。有时被称为“免费搭车”的做法可能最终会给创新型公司和公共卫生带来红利。具有讽刺意味的是，对扩大数据访问权最为抵触的组织，恰恰也是能从更高透明度中大量获益的组织。

述评作者Hans-Georg Eichler博士、Frank Petavy、Francesco Pignatti博士和Guido Rasi博士均供职于欧洲药品管理局。

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By: ALICIA AULT, Cardiology News Digital Network

Clinical trial data should be shared as broadly as possible to help spur scientific innovation and answer questions of importance to public health.

"The question is not whether, but how, these data should be broadly shared," wrote Michelle M. Mello and her colleagues from Harvard University, Boston, the Pharmaceutical Research and Manufacturers of America, and several consulting companies, in an article published online Oct. 21 in the New England Journal of Medicine.

At a minimum, data-sharing should be available for trials of all approved prescription drugs, devices, and biologics in any country that has adequate intellectual property protection. A system has to ensure responsible use of data, protect privacy of research participants, and treat "all qualified data requesters and trial sponsors evenhandedly," requiring both generators and requesters to work according to the same rigorous scientific principles (N. Eng. J. Med. 2013 Oct. 21 [doi: 10.1056/NEJMhle1309073]).

The demand for more data from and about clinical trials – including protocol designs, results summaries, and more recently, raw input data – has grown over the past 15 years. Some medical journals have pushed for disclosure of more data upon request. The Food and Drug Administration increasingly has been requiring disclosure, and pharmaceutical manufacturers in the United States and Europe have made commitments to making more information public. Beginning in March 2014, the European Medicines Agency will require disclosure of some raw data, individual case report forms, and other data.

The authors envision at least four potential models for sharing data. With purely open access, everything would be available for download for free. This is the riskiest model, they said, since it would provide the least accountability.

Another model: The data generator would keep the data but answer very specific requests. A third model would have the clinical trial sponsor review data requests and decide whether and how to release the data.

In the last model, an independent review board would determine whether the data should be released. The board would collect the data from the sponsor and issue it to the requester, on a limited, need-to-know basis.

This model would likely best balance all of the competing needs, according to the authors. The independent board promises "to ensure accountability on the part of data generators and users and allow trial sponsors a voice while precluding them from denying access to data for reasons the public would not consider legitimate," they wrote.

An independent board also would help protect research participants and make sure that the playing field is level among all stakeholders, they added.

The authors noted many benefits to allowing wider access to patient-level data, such as independent analyses of safety and effectiveness, new lines of inquiry that could expose product flaws or trial design flaws, and the potential to answer questions that might affect public health but that weren’t explored in the original study.

The biggest downside is that individual participants’ privacy could be compromised, according to the authors. The risk of exposure "raises critical questions about how to ensure that participants understand the potential ramifications of data sharing," they wrote.

Mandatory disclosure could also discourage investment in research and development if manufacturers believe that the data could be used by competitors. Wider data-sharing could also lead to second-guessing of approvals by regulatory agencies.

Clinical trial data-sharing received attention from the World Medical Association in its most recent update of the Declaration of Helsinki, published online Oct. 19 in JAMA (doi: 10.1001/jama.2013.281053). Three general principles addressed data sharing:

· Number 9: It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for the protection of research subjects must always rest with the physician or other health care professionals and never with the research subjects, even though they have given consent.

· Number 24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal information.

· Number 32. For medical research using identifiable human material or data, such as research on material or data contained in biobanks or similar repositories, physicians must seek informed consent for its collection, storage and/or reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain for such research. In such situations the research may be done only after consideration and approval of a research ethics committee.

Several of the authors of the paper published in the New England Journal of Medicine disclosed that they work for consulting companies that receive fees from various manufacturers and from academic medical centers. The working group was convened through the Multi-Regional Clinical Trials Center at Harvard University, which receives funds from pharmaceutical companies and not-for-profit entities.

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Data sharing will help research

Contrary to industry fears, we argue that access to full – though appropriately deidentified – data sets from clinical trials will benefit the research-based biopharmaceutical industry. We predict that it will help to increase the efficiency of drug development, improve cost-effectiveness, improve comparative-effectiveness analysis, and reduce duplication of effort among trial sponsors.

A managed-release environment that allows sharing of patient-level data while ensuring patient privacy would create a level playing field for all stakeholders. What is sometimes labeled as "free riding" may ultimately pay dividends for innovative companies and for public health. It is ironic that the organizations that most resist wider access to data are the ones that stand to benefit so much from greater transparency.

Dr. Hans-Georg Eichler, Frank Petavy, Dr. Francesco Pignatti, and Dr. Guido Rasi are all with the European Medicines Agency in London. Their remarks are taken from an accompanying editorial(N. Eng. J. Med. 2013 Oct. 21 [doi: 10.1056/NEJMp1310771]).