Dr. Robert Califf 国际著名心血管疾病专家，去年走马上任掌管全球更大的食品药品监管机构——FDA。他从监管法规的角度评述心血管疾病的未来，这是他多年临床与转化医学领域丰富经验，更重要的是他的全球化视野和全息洞察能力。
2012年，我邀请Dr. Califf在第三届中美与临床与转化医学国际论坛上讲述一下创新药物早期临床试验的成功经验，他说“你知道中国足球队吧？（哪壶不开提哪壶） 为什么所有人都关心进球？没有人总结不进球数（的原因）？” “新药研发成功案例讲多了，人们感觉创新药没什么难的，我还是讲讲失败案例吧！” 果然，他以他特有的观察角度，例举了新药研发过程中失败教训和瓶颈，以及如何从中汲取经验（不谈国足，看看女排就可以了）。
上周，Dr. Califf 发表了一篇评述文章。他从监管法规角度归纳和梳理了心血管疾病的未来。为更准确地理解内容和意义，在此提供原文供各位参考。
Dr. Califf 的观点一
不可阻挡趋势
1）生物学和信息科学的发展形成了信息流，融入我们每一天的工作和生活；2）各种社交媒体和智能终端传播和获取信息之巨大，我们任何人都无法回避和忽视这些趋势了。
随着先进科技成果的转化应用，今天的心血管疾病专家使用的医疗设备不仅可以延缓患者疾病，还有可能治愈并让患者恢复正常工作和生活。医生们已不再质疑“这个能行吗？” 更多情形是“用哪个更好？”
Dr. Califf 的观点二
现实中的确有更多、更好的治疗选择，但是，若使用不当或过度使用，也会给患者带来风险，甚至适得其反。特别是在没有足够循证依据，没有临床指南情形下，再先进技术和设备也可能无济于事。
Dr. Califf 的观点三
老龄群体是缺少循证研究的群体——我们没有足够的科学数据来证明如何关照老人的医疗和健康管理。多数情况下，是凭想象指导老人服药剂量和用法。如同儿童用药和剂量一样。许多临床试验不会招募入组75岁以上老龄患者，但他们的临床治疗恰恰是我们最需要的数据。
Dr. Califf 的观点四
心血管疾病临床诊疗一直是循证实践的“典范”，然而，事实上也只有不到15%的临床诊疗指南来源于高质量、高水平的循证数据和实践。又有多少医生在临床实践中遵循这些指南和治疗规范呢？这不是FDA的职责范围，但是患者的治疗安全问题。扎实的循证临床数据可以避免盲目追捧新技术和新 *** ，在这方面急需加强。
例如：近年来越来越多瓣膜病变诱发的心脏疾病采用置换人工瓣膜疗法。对部分患者来讲，的确起到了起死回生的效果，然而又有多少循证研究证明哪些患者需要？这是心血管疾病专家对心脏病所谓“严重程度”的理解和诠释差异。这里有FDA的责任和义务提示人工瓣膜的适应范围和应用，也有心血管疾病专家的认知问题。
Dr. Califf 的观点五
在心血管疾病领域，医疗器械或设备的创新研发和转化应用起了至关重要的作用。例如：心脏支架的发明和应用，救活了成千上万名猝发心梗患者或潜在心梗患者。同样是该领域，依然缺乏足够循证研究来说明哪些器械和设备是有效和必要的（有时侯放支架3个、5个或7-8个都有）。
这里有FDA难言之隐，医疗保险公司并不认可那些花里胡哨设备的实际价值和意义。为此，有人感觉FDA对那些最新、最前沿的设备和器械审评过于宽松或严格。
最后，Dr. Califf 支持“付费参与临床试验和循证研究”的做法。这样一来，不仅保护了创新研发，同时也能回答患者和医疗保险机构对临床研究安全性的担忧。
总之，监管法规源于循证数据和科学验证。临床效果同样也需要患者的疗效反馈信息和诊疗数据。FDA在心血管疾病领域的改革方向和未来发展趋势——想让FDA批准你的产品上市？拿出循证数据来！
原文如下（省略参考文献）
九月份沙龙和培训项目：
邀请：REDCap临床试验数据管理和云平台高级培训班
医境?逸景沙龙：2016年诺奖和拉斯克奖的“获奖者”
邀请：第七期《远程医疗实践规范和指南》研修班
邀请：2016美国远程医疗协会(ATA)秋季年会预告
中文版REDCap临床试验数据管理和云平台培训班开始【邀请函】
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For many years, the American public and theentire world have benefited from the U.S. Food and Drug Administration’s (FDA)regulatory system for medical products. The field of cardiovascular medicinehas been an exemplary partner with the FDA for much of this time—a periodmarked by advances ranging from better diet to life-saving drugs, devices, andbiologics, ultimately resulting in a nearly 40% reduction in the risk of deathfrom cardiovascular disease in the first decade of the 21st century(1). Largely due to the confluenceof the FDA’s standards for evidence and wise leadership withinthe field, cardiovascular medicine has one of the strongest evidence basesamong specialties (2). Patients, physicians, and the public canhave confidence in medical products used to prevent and treat cardiovasculardisease because FDA standards for safety and effectiveness have been met, andalso because the highly evolved approach to applying professional clinicalpractice guidelines in cardiovascular medicine provides important and usefulclinical context for the use of medical products and behavioralinterventions.
We are now entering a new era in medicine that ischaracterized by dramatic accelerations in biological and information sciencesand near-ubiquitous uptake of social media and personal devices. Together,these advances make possible the integration of complex measurement anddecision support with traditional devices, drugs, and biologics to producepowerful interventions that can be evaluated much more rigorously andefficiently. But the potency and integrated nature of these interventions alsoincrease the potential for harm if they are used inappropriately or if theirdevelopment plans do not generate the evidence needed to guide practice,tipping the balance of risk and benefit in an unfavorable direction.
The FDA is responding to this changing world. However, webelieve the needed changes must involve not only the FDA but the entireecosystem of which the FDA is a part. As we work together to shape the futureof medicine, cardiovascular specialists will play a special role.
循证依据
The cardiovascular community has been a leader in evidence-basedmedicine, yet only about 15% of its major practice guideline recommendationsare currently supported by high-quality evidence (3,4). However, dramatic improvements in the rate, quantity, and quality of evidence generation are within reach. Almost all Americans now have electronic health records, and social media combined with wearable devices are opening new frontiers in patient- and population-level data. In addition, registries forquality and care delivery are proliferating, with efforts by the Society of Thoracic Surgeons, the American College of Cardiology, and the American Heart Association setting the standard for other specialties. Keeping pace with rapid technological change will present a key challenge, and it will be criticalfor the FDA and the cardiovascular community to continue working together tocreate an evidence-generation system capable of guiding practice in the coming years.
表型
A remarkable opportunity now exists to characterize states of health and disease in human populations using intensive and continuous measurements. Cardiovascular disease is marked by complex, multifactorial phenotypes such as those presented by vascular disease and heart failure. Untilrecently, we were limited by our inability to measure genes and their downstream molecular products. Furthermore, the integration of molecular and physiological knowledge was thwarted by our inability to store, curate, and *** yze sufficiently large quantities of data.
Those limitations are rapidly dissipating. Now is the time for cardiovascular researchers to develop approaches to using the full arm amentarium of genetic, genomic, physiological, imaging, and clinical measurements to understand the interplay of factors that drive clinicaloutcomes and therapeutic effects. From the FDA’s perspective, better phenotyping would yield much more informative early-phase clinical trials and facilitate detection of therapeutic benefit and off-target toxicities earlierin the development process.
复合型生物标志物和监测
Despite substantial advances in biomedical knowledge,clinical decision making still relies on bedside heuristics. Unfortunately, the human brain is not well configured to integrate multiple streams of information, particularly when collected over time, into crisp decision making. Proliferating measurement methods have created a deluge of proposed biomarkers, often accompanied by unrealistic expectations and exaggerated claims ofutility. However, the same methods that will drive effective phenotyping c *** so sort out which biomarkers have utility for particular purposes. The FDA and National Institutes of Health (NIH) are collaborating on the Biomarkers, Endpoints and other Tools (BEST) online resource (5),which will provide researchers, technology developers, and clinicians withclear definitions and other information on the development of biomarkers and outcome measures.
A critical feature within this evolving landscape is the profusion of personal electronic devices and applications that can measure heart rate and rhythm, blood pressure, and physical activity, and capture preferences and social activity using geospatial referencing. When combined with modern informatics and computing resources, this rich tapestry of information will enable a true paradigm shift, replacing the “1 biomarker at a time” approach with algorithms that integrate multiple measures to predictoutcomes, diagnose and classify disease, and tailor treatment to the individual. The FDA is actively working on approaches to regulation that can both accommodate this complexity and promote useful innovation by moving to quality systems and standards-based regulation in much more transparent platforms.
靶向治疗
Major advances in cardiovascular medicine have come frombroad-spectrum therapies deployed to large populations to treat such common problems as hypertension, hyperlipidemia, and glucose intolerance. Although thepast year has seen even more effective therapies for hyperlipidemia and heart failure approved for market (6–8), it seems likely that many broad risk factors have underlying biological elements that will eventually guide more refined targeting of therapies.
医疗器械
Devices including physiological monitors, pacers, cardioverter/defibrillators, and stents have been an important part of cardiovascular medicine’s success. The FDA has focused on developing efficient pathways across all phases of product development and throughout the product lifecycle. We now need cardiovascular specialists and major institutions withexpertise to join together to create effective networks for conducting early device feasibility studies with a high degree of technical competence and attention to ethical considerations, in conjunction with FDA oversight through the investigational device exemption (IDE) regulations (9).
The later phase of cardiovascular device development iscomplicated by the intersection of research and payment systems. Building onthe extensive availability of high-quality registries, the FDA is developing an approach that would allow existing data to be leveraged in a way that couldlower the cost of premarket trials. Additional evidence can be generated with the “coverage with evidence development” (CED) system (10), in which payment is conditional upon participation in a study to generate needed benefit/risk information. As unique device identifiers (11)are phased in, it will be possible to measure device-related outcomes across the product lifecycle using a combination of registries, electronic health records, and claims data, as described in our plans for the National Evaluation System for healthcare Technology (NEST) (Shuren J, Califf RM, in press, July 2016).
再生医学
The use of human tissue and the modification of somaticgenetic material are exciting technologies with the potential for an enormous impact on disease outcomes. Currently, however, much cell therapy is being administered in hospitals without the benefit of systematic frameworks such as those provided by the national quality and delivery systems in place for pharmaceuticals and devices (12,13). As the science matures, there will be many opportunities to attempt to fundamentally change the trajectory of disease, including through organ replacement, processed stem cells, and tissue scaffolding. In many cases, short-term effects may pale in comparison to long-term effects, because theregenerative process could last a lifetime.
营养和膳食
What should we eat to optimize health and quality of life? This may be the question most commonly asked of doctors. However, the specific answer to this question is not always certain, and major miscues, including broad recommendations about intake of cholesterol and carbohydrates, have undermined public confidence and created opportunities for self-styled experts to profit from dubious advice (14). But as our capacity for generating evidence across large populations continues to improve, so will our ability to conduct quantitatively rigorous observational and experimental studies in this challenging arena. The FDA iswell positioned to leverage the expertise of the Center for Food Safety and Applied Nutrition to consider these issues.
生命周期
As our knowledge continues to expand, it has become clear that we need to focus on both ends of the lifespan. Major diseases of neonates and children—which affect >1% of the population—include congenital heart defects and diseases with a primary or major secondary cardiovascular manifestation, and pose special issues, such as how to weigh the benefits and risks of broad preventive efforts in the face of uncertainty. Legislativeaction (15,16) has had a significant impact on the development of evidence to support therational use of drugs in children. We now need to focus on devices, where *** aller pediatric populations do not generate enough incentives for development of pediatric-specific devices despite inducements provided in the Humanitarian Device Exemption.
There is also a pressing need to better understand medications in pregnant women. Concerns about liability and risk have created asituation in which very few medicines are studied adequately for effects onpregnant women, lactating mothers, and the fetus or infant. Yet, we have ageneration of women with *** congenital heart disease and other chroniccardiovascular diseases who must take medications while pregnant. The FDA and the cardiovascular community must work together to rectify this problem.
Elderly patients—particularly those >80 years ofage—represent another underserved population. Although many interesting observational studies have been done, we have a real deficit in knowledge pertaining to proper dosing of therapies in elderly patients, or when invasive procedures are indicated.
贫富差距
Despite all the investigations of health and health care disparities, we continue to see enormous differences in lifespan and quality oflife as a function of demographics. On a global basis, life expectancy is much shorter in low-income countries compared with wealthy countries, and an increasing component of this disparity is due to cardiovascular disease. With in the United States, similar disparities are seen according to geographiclocation, race, and income down to the level of individual neighborhoods (17). Although 90% of U.S. preions are generic, and most essential cardiovascular medicines are inexpensive, problems with access and adherence to these medications remain, especially in underserved communities. Moreover, there is also ample evidence of similar disparities in access to surgical treatment (18).The FDA welcomes collaborative work aimed at addressing these issues.
结论：
The partnerships between the FDA and multiple communities of stakeholders have successfully reduced death and disability from cardiovascular disease. Now, ingenious research and technology development, combined with general advances in biological and information technologies, will further accelerate improvement in outcomes. But if we are to harness these technologies and apply them effectively, our systems for evidence generation and healthcare delivery must continue to improve in concert with drugs, devices, and biologicalproducts.
参考文献：
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