4. FDA and MHRA Discuss Data Integrity (Jan 2020)
FDA和MHRA关于数据完整性的讨论（2020年1月）
Summary:
Officials from the FDA and the MHRA provided a summary of their first GCP workshop held in Oct 2018 in an article published in Clinical Pharmacology & Therapeutics. FDA and MHRA will hold another joint GCP workshop in Feb this year to further discuss these issues. International regulatory collaboration on good clinical practice (GCP) has become critical for adequate oversight and the assessment of data integrity because of the increasing numbers of clinical trial sites per study, their locations outside the regulatory agencies’ regions, the limited resources of such regulatory agencies and the accelerated timelines by which regulators have to review marketing applications.
摘要：
FDA和MHRA的官员在Clinical Pharmacology & Therapeutics发表了一篇关于他们在2018年10月首次举办的GCP研讨会的总结文章。FDA和MHRA将在今年2月召开另一个GCP 联合研讨会就这个话题进一步探讨。药物临床试验质量管理规范（GCP）方面的国际监管合作对于充分监督和数据完整性评估至关重要，因为每项研究的研究中心数量不断增加，研究中心位于监管机构地区以外，此类监管机构资源有限并且监管机构必须加速完成上市申请的审查。
Although international collaboration is key to ensuring the safety of clinical trials, the authors also explain some of the differences among regulators.
· EMA inspections: are focused on GCP systems and processes in clinical trials and grade each finding and cite ICH E6 (R2) on GCP noncompliance.
· FDA inspections: take an outcome-focused approach, focusing on data line listings to verify data provided in marketing applications and cite 21 Code of Federal Regulations (CFR).
虽然国际合作是确保临床试验安全性的关键，但作者也解释了监管机构之间的一些差异。
· EMA检查：重点关注临床试验中的GCP系统和流程，对每个发现进行分级，针对GCP不合格项将使用ICH E6（R2）进行评价。
· FDA检查：采取注重结果的方法，重点是数据列表，以核实上市申请中提供的数据，并引用联邦法规（CFR）21条。
Some Key Topic Areas discussed where:
· The Importance of Quality and Risk Management Systems
· Globalization of Clinical Trials and International Collaboration
· Effective Use of Audit Trials
· Protecting the Study Blind
· Data Management
o Source Data at the Clinical Investigator Site
o Data Modifications
o Clinical Investigator Control of their Data
o eSystems Consistent with the final approved protocol
o eCRF with IRT Integration
o eSystem Validation
o Contracts between eSystem Providers and Sponsors
o Database Lock
o Protocol and GCP Non-Compliance
o Retention of Data and Documentation
o Data Quality
o Data Management Plan
· Provided examples of the following types of unblinding cases:
o Adverse Events associated with the IMP
o Randomization Documentation
o Electronic Systems used in the study
o Data Management Practices
o Third Party eSystems
o Handling of Blinding Codes in Bioequivalence Studies
一些关键主题讨论了以下几点：
· 质量和风险管理体系的重要性
· 临床试验全球化与国际合作
· 有效使用稽查轨迹
· 保护研究盲态
· 数据管理
o 临床研究中心的源数据
o 数据修改
o 临床研究者对其数据的控制
o eSystems与最终批准的方案一致
o eCRF与IRT整合
o eSystem验证
o eSystem提供商和申办方之间的合同
o 数据库锁定
o 研究方案和GCP不依从
o 数据和文件的保留
o 数据质量
o 数据管理计划
· 提供了以下揭盲病例类型的示例：
o 与IMP相关的不良事件
o 随机化记录
o 研究中使用的电子系统
o 数据管理实践
o 第三方eSystem系统
o 生物等效性研究中设盲代码的处理
Key Takeaways:
· As clinical trial methodologies and new technologies are deployed, data integrity and the safety of clinical trial participants remain at the forefront of regulatory oversight.
· International collaboration provides a pathway to enhance regulatory oversight to assure data integrity and the safety of subjects enrolled in clinical trials.
· During the workshop concerns with audit trails, blinding and data management overall have been presented as well as potential measures to prevent or mitigate the impact of the data integrity concerns.
关键信息：
· 随着临床试验方法和新技术的部署，数据完整性和临床试验参与者的安全性依然是监管的重心。
· 国际合作为加强监管提供了一条途径，以确保数据完整性和临床试验入组受试者的安全性。
· 在研讨会期间，对稽查轨迹、盲法和数据管理以及防止或减轻数据完整性问题影响的潜在措施进行了介绍
References:
FDA, MHRA Officials Stress the Criticality of Data Integrity in Clinical Trials – Regulatory Focus
5. FDA Announces Key Actions to Advance Development of Novel Coronavirus Medical Countermeasures (Jan 2020)
FDA宣布推进新型冠状病毒医学对策研发的关键举措（2020年1月）
Summary:
The US FDA has issued a statement explaining how the agency can facilitate the development of investigational products to diagnose, treat and prevent emerging public health threats such as the novel coronavirus (2019-nCoV) that emerged in Wuhan, China in December. In order to support efficient medical product development for novel coronavirus medical countermeasures, today the FDA is launching a landing page that provides key information for the public, including product developers, on the FDA’s efforts in response to this outbreak.
摘要：
美国FDA已发布声明，解释该机构如何促进用以诊断、治疗和预防新出现的公共卫生威胁，如12月在中国武汉出现的新型冠状病毒（2019-nCoV），的研究产品的开发。为了支持针对新型冠状病毒的医疗产品的高效开发，今天FDA启动一个登陆页面，为公众（包括产品开发人员）提供了有关FDA努力应对此次疫情的关键信息。
FDA says it may grant emergency use authorizations (EUA) to medical countermeasures, such as diagnostics and therapeutics under Section 564 of the Federal Food, Drug, and Cosmetic Act.
· However, before FDA can issue an EUA, either the Department of Defense (DoD), Department of Homeland Security (DHS) or Department of Health and Human Services (HHS) Secretary must issue an emergency or material threat determination. After one of those determinations is made, the HHS Secretary must issue an emergency declaration justifying emergency use of unauthorized products or unapproved uses of authorized products.
· While FDA cannot currently issue an EUA, the agency directs diagnostics developers to contact the Center for Devices and Radiological Health for information and templates for submitting a pre-EUA and requests that therapeutic sponsors contact the Center for Drug Evaluation and Research’s pre-investigational new drug consultation program.
· According to FDA, a pre-EUA “allows FDA scientific and technical subject matter experts to begin a review of information and assist in the development of conditions of authorization, fact sheets, and other documentation that would be needed for an EUA in advance of an emergency and also helps to facilitate complete EUA requests during a current emergency declaration,” but notes that a pre-EUA cannot transition to an EUA without an emergency declaration from the HHS Secretary.
FDA表示，对于如联邦食品，药物和化妆品法案第564节所列的诊断和治疗等医疗对策，它可以授予紧急使用授权（EUA）。
· 但是，在FDA发布EUA之前，国防部（DoD）、国土安全部（DHS）或卫生与人类服务部（HHS）部长必须发布紧急威胁决定或物资威胁决定。在作出其中一项决定后，HHS部长必须发布紧急声明，证明紧急使用未经授权的产品或未经批准的授权产品的合理性。
· 虽然FDA目前无法发布EUA，但该机构指示诊断开发人员与设备和放射健康中心联系，获取提交预先EUA的信息和模板，并要求申办方联系中心，了解药物评估和研究的预研新药咨询计划。
· 据FDA称，预先EUA“允许FDA的科学和技术专家提前开始审查信息，并协助制定授权条件，概况介绍和其他EUA需要的文件，并还有助于在当前紧急声明期间促进完成EUA申请“，但请注意，如果没有HHS部长的紧急声明，预先EUA不能过渡到EUA。
There are currently no FDA-approved diagnostics, vaccines or drugs for 2019-nCoV, though several drug makers and diagnostics developers have said they are working on vaccines and tests. The National Institutes of Health (NIH) has also partnered with Massachusetts-based biotech company Moderna to develop an RNA vaccine against the virus.
目前还没有FDA批准的2019-nCoV诊断制剂，疫苗或药物，尽管有几家制药公司和诊断制剂开发商表示他们正在研究和测试疫苗。美国国立卫生研究院（NIH）还与位于马萨诸塞州的生物技术公司Moderna合作开发了一种针对该病毒的RNA疫苗。
Key Takeaways:
· FDA states they have begun employing a full range of our public health authorities to facilitate the development and availability of investigational medical products to address this urgent public health situation.
· The FDA will collaborate with interagency partners, product developers, international partners and global regulators to expedite the development and availability of medical products needed to diagnose, treat, mitigate and prevent such outbreaks.
关键信息：
· FDA表示，他们已经开始启用全方位的公共卫生机构来促进研究性医疗产品的开发和供应，以解决这种紧迫的公共卫生状况。
· FDA将与跨部门合作伙伴，产品开发人员，国际合作伙伴和全球监管机构合作，加速诊断，治疗，缓解和预防此类疫情所需的医疗产品的开发和供应。
References:
FDA Outlines Product Development Process to Combat Wuhan Coronavirus – Regulatory Focus
6. FDA "CDER Conversation" on Real World Evidence - From Safety to a Potential Tool for Advancing Innovative Ways to Develop New Medical Therapies (Feb 2020)
FDA关于真实世界证据的“CDER对话”——从安全性到推进创新方法开发新的医疗疗法的潜在工具（2020年2月）
Summary:
The FDA recently posted a “CDER Conversations” blog on Real World Evidence - From Safety to a Potential Tool for Advancing Innovative Ways to Develop New Medical Therapies. In this blog 2 FDA employees were interviewed on the topic. Jacqueline Corrigan Curay, MD, JD. Director of Office of Medical Policy, CDER and David Martin, MD, Associate Director for Real World Evidence Analytics, CDER. Some highlights of the article are noted below:
摘要：
FDA近日在博客上发表“CDER对话” 真实世界的证据-从安全性到推进创新方法开发新的医疗疗法的潜在工具. 在这个博客中，2名FDA员工接受了该主题的采访，分别是Jacqueline Corrigan Curay，医学博士，JD.，CDER医疗政策办公室主任，以及David Martin博士，CDER真实世界证据分析副主任。文章的一些亮点如下所示：
In order to examine if, and under what circumstances, non-interventional RWE can provide credible evidence of drug effectiveness, FDA and other stakeholders are designing RWE studies that ask questions similar to ongoing or completed clinical trials and comparing results.
1. The RCT Duplicate Project, is attempting to duplicate the results of recently completed clinical trials using RWE studies.
2. Another project with the Yale-Mayo CERSI will attempt to duplicate several more trials using medical claims and electronic health record data.
为了测试非干预性RWE是否以及在何种情况下可以提供可靠的药物有效性证据，FDA和其他利益相关方正在设计RWE研究，研究提出类似于正在进行或已完成的临床试验的问题，并将对RWE和临床试验的结果进行比较。
1. RCT重复项目，试图使用RWE研究复制最近完成的的临床试验的结果。
2. 另一个与 Yale-Mayo CERSI 合作的项目，将尝试使用医疗索赔和电子健康记录数据复制更多的试验。
Examples of Using RWE and RWD in drug approvals and regulatory decisions:
1. CBER approved a vaccine for shingles, where there was limited long-term data on effectiveness in the 50-59-year-old population.
· The sponsor undertook a prospective, observational study in which patients who received the shingles vaccine as part of normal care were followed over time to see if the vaccine prevented shingles. The data were provided to FDA and the approved label was updated with longer-term effectiveness data.
2. Researchers studied whether FDA-approved drugs used to treat attention deficit-hyperactivity disorder (ADHD) could cause serious cardiovascular events in children and young adults.
· A clinical trial to test these drugs for this adverse event presented many challenges. For instance, because serious cardiovascular events are rare in this patient population — only about 3 in every 100,000 children per year — a clinical trial would have had to have been unfeasibly large to assess a potential drug effect.
· Instead, using electronic health care data from four health plans, researchers studied RWE for more than a million children and young adults and the results suggested that current users of drugs for ADHD did not have an increased risk of serious cardiovascular outcomes.
3. RWE to establish effectiveness is still an emerging science, but there are some examples where historical controls were derived from RWD.
· Blinatumomab, approved in 2014 under the trade name Blincyto for a type of blood cancer called acute lymphoblastic leukemia (ALL), was approved initially under accelerated approval based on a single-arm trial where everyone received the experimental therapy, and evidence of effectiveness was based on complete remission (CR) and duration of CR. This response to the drug was compared to the records of a population of patients not treated with the drug at several U.S. and European clinical centers. The clinical benefit of the drug was subsequently established with a randomized clinical trial against standard of care establishing a benefit in overall survival.
· In addition, when Myozyme was approved for Pompe disease, it was based on a study of comparing survival and rate of ventilator support in 18 patients who received Myozyme compared to a historical control group of 62 patients derived from medical charts.
在药物批准和监管决策中使用RWE和RWD的例子：
1. CBER基于有限的50-59岁人群的长期有效性数据，批准了一种带状疱疹疫苗。
· 申办方进行了一项前瞻性观察性研究，对接受带状疱疹疫苗作为正常医疗护理的一部分的患者进行了长期随访观察，以查看疫苗是否预防带状疱疹。数据提供给FDA，批准的产品说明书根据长期有效性数据进行了更新。
2. 研究人员研究了FDA批准的用于治疗注意缺陷多动障碍（ADHD）的药物是否会导致儿童和青壮年严重的心血管事件。
· 测试这些药物是否具有此类不良事件的临床试验面临诸多挑战。例如，由于严重的心血管事件在该患者群中很少见 – 每年每100,000名儿童中仅有三例发生 – 临床试验必须具备难以达到的大样本量才可能评估潜在的药物反应。
· 相反，研究人员利用四项健康计划的电子医疗保健数据，研究了100多万儿童和年轻人的RWE，结果表明，目前使用ADHD的药物没有增加使用者出现严重心血管结局的风险。
3. 通过RWE建立有效性仍然是一门新兴的科学，但有一些历史对照来源于RWD的例子。
· Blinatumomab于2014年获批，商品名为Blincyto，用于治疗一种名为急性淋巴细胞白血病（ALL）的血癌，最初的加速批准是基于单臂试验的结果，即每个人都接受了试验治疗，有效性的依据基于完全缓解（CR）和CR的持续时间。将这种对药物的反应与数个美国和欧洲临床中心未接受该药物治疗的患者群体的记录进行比较。临床益处的确定基于一项随后开展的以标准治疗为对照的随机临床试验，即该治疗有益于总生存期。
· 另外，批准Myozyme用于庞培病是基于一项18名接受Myozyme的患者的存活率和呼吸机支持率，与来自医疗记录的62名患者的历史数据作为对照组相比较的研究结果。
Limitations in using RWD/ RWE:
· The biggest challenge is that RWD is not intended for research. Much of the RWD that we are seeking to use comes from medical records designed for physicians taking care of their patients — and what they put in the chart is what they think is important. Although there is some consistency with how physicians record their patient care activities, there's probably more inconsistency than consistency.
· Unstructured data, like doctor’s notes, and scanned reports are more difficult to harmonize across systems without additional curation of some kind, and in many cases, we may need to connect the dots (really datapoints) to get a full picture of a patient’s experience. Sharing this data among different electronic systems holds promise but is not fully developed.
使用RWD/RWE的限制：
· 最大的挑战是RWD不是以研究为目的。我们寻求使用的大部分RWD来自为医生治疗患者而设计的医疗记录-医疗记录的内容是他们认为重要的内容。虽然医生如何记录他们的病人医护活动有一些一致性，但很可能不一致性多于一致性。
· 非结构化数据，类似医生的笔记、扫描的报告，若不采取额外的策略，很难在系统间达到协调一致。许多情况下，我们可能需要将这些点（真正的数据点）连接起来，以获得患者经历的全貌。有希望在不同的电子系统之间共享这些数据，但这些系统目前尚未完全开发。
Key Takeaways:
· RWE has long been used to assess safety issues but it’s relatively new for studying the effectiveness of drugs. In the area of effectiveness, one challenge that limits the use of RWE is that the clinical measures that are used to determine whether a drug is effective are either not used in clinical practice or are not captured consistently and at time points that enable an accurate assessment of effectiveness.
· As the FDA uses RWE studies in its decision-making process, more companies may be likely to conduct RWE analyses, strengthening this area of research.
关键信息：
· RWE长期以来一直用于评估安全问题，但用于评估研究药物的有效性为时尚短。 在有效性领域，面临的一个挑战是用于确定药物是否有效的临床测定方法要么不在常规临床实践中使用，要么未能在能够对有效性进行准确评估的时间点上获得一致的记录，这将限制对RWE的使用。
· 由于FDA在决策过程中使用RWE研究，更多的公司可能会进行RWE分析，从而加强这一领域的研究。
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