骨科研究学会成员在一个关于如何避免在新产品和新治疗发展过程中走弯路的临床研究论坛中，将重组人骨形态发生蛋白-2（rhBMP-2）列入议程。尽管最近各种报道指出产业资助试验的结果遭到抨击，“标签外使用”药物仍广受关注。

    克利夫兰市的临床医师Thomas Mroz博士提出一些和“标签外使用药物”（也称内科医师直接使用的药物）相关的议题。

    BMP在1965年由Marshall Urist博士发现，但直到2002年，它的一种形式——rhBMP-2才被美国FDA批准使用，而且只能和LT-Cage（美敦力公司）用于单节段的腰椎前路融合术中，而在其它任何手术——包括颈胸椎融合、后外侧、后路和经椎间孔腰椎融合术中的使用仍未被临床试验认可。FDA章程和其它适用法律允许内科医师根据其灵通的药物判断患者的最大利益，以此开出或授权任何合法市场推广这种“标签外使用药物”。

    史坦佛大学的Eugene J. Carragee博士提出这些药物很多都是标签外使用并且大剂量使用。Mroz 博士引用了其提出的问题，反问道：“如果该类药物有效，那问题是什么？”其并发症包括神经炎性反应、逆行射精和脊神经根炎、感染和伤口问题、致癌或促癌。

Mroz博士从销售数据中估计2011年大约有165,000名患者使用rhBMP-2，而且今年还将有148,000人使用。他估计2/3为“标签外使用”使用。例如，最近一项对Spineline杂志读者的调查显示，大部分支持rhBMP-2的医生将其用于各种“适应症外”的手术。

    获得该产品安全性和有效性数据的常用方法是文献回顾，但Mroz博士指出这种综述是基于少部分入组研究的患者，而不是实际上众多使用该药物的患者。另外考虑的问题是研究设计、报道、实践相当大的不均一性以及Carragee博士概括出的利益冲突问题。

    “注册和保险数据库很有可能用于随访大量的患者”，Mroz博士说。理论上的优点包括潜在的可收集资料和在临床应用中方法技术应用的跟进。该数据库还将使跨时间和跨区域的适应症监控以及结果对照成为可能。然而他也指出，该数据库的管理复杂且昂贵。“设计很简单，但实施却很复杂，”他说。

更多透明度

    医学博士、工商学管理硕士Kevin J. Bozic在对rhBMP-2产业试验评价的概述中，第一次指出产业介入的优点是它能提供资金、基础设施和承担创新风险。

    “内科医生中的创新者很自然的不愿承担风险，而产业却能为其创新提供提供资金、基础设施和并愿意承担风险，因此使之获益。”他说。Bozic医师同时也指出器械产业为临床试验提供很多必需的支持。

    但是，围绕临床试验的产业资金投入仍受到很多关注，包括产业对研究者选择的影响、研究设计和结果的宣传。

    研究者的产业选择会导致研究结果的偏差，Bozic医师指出，接受了咨询和使用费的外科医生常常会因为经济冲突而影响他们的客观性，从而影响临床试验的结果。这样就会影响到那些阅读关于产业资助临床试验的结果文章的人，而“思想领袖”的意见往往会对临床医生造成很大影响。

无论是否真的存在，公众都认为产业资助的试验存在偏差。根据其发布的结果，Bozic医师指出产业资助的研究是专有的，并不需要出版和传播，许多临床试验从不发表，就算在发表的试验中，也不是将所有的数据公布。

    Bozic医师主持了耶鲁大学数据公开分析计划(YODA)的临床指导委员会，会议试图解决临床研究的产业资助方面的一些关注问题。该计划由研究中rhBMP-2的生产商美敦力公司赞助，其既定目标是“通过促进对药物和设备优劣相关数据独立的分析和传播机制，来增加透明度并增强公众对产业资助临床试验的信心。”

Terry Stanton

During a clinical research forum on ways to avoid wrong turns in the development of new products and therapies, members of the Orthopaedic Research Society included the issue of recombinant human bone morphogenetic protein–2 (rhBMP-2). Although various aspects of reporting the results of industry-sponsored trials have come under fire recently (See “Lessons Learned: What the BMP Trials Controversy Has Taught Us” in The Daily Edition—AAOS Now, Feb. 9, 2012), concerns about “off-label” use were also raised.

Thomas Mroz, MD, of the Cleveland Clinic, addressed some general issues associated with off-label—also called “physician-directed”—use.

BMP was discovered in 1965 by Marshall Urist, MD, but it was not until 2002 that one form, rhBMP-2, was approved by the U.S. Food and Drug Administration (FDA)—for use, and only in one-level anterior lumbar interbody fusion with an LT-Cage (Medtronic). Its use in any other procedure—cervical and thoracic fusions, posterolateral, posterior and transforaminal lumbar interbody fusions—is off-label. FDA regulations and other applicable laws recognize that physicians may prescribe or administer any legally marketed product for an off-label use, according to the physician’s well-informed medical judgment for the best interest of the patient.

Asking rhetorically, “If it works, what’s the problem?” Dr. Mroz cited the numerous problems previously detailed by Eugene J. Carragee, MD, of Stanford University, noting that many of them occurred in off-label usage and with high-dose usage. These complications included neuroinflammatory reactions of retrograde ejaculation and radiculitis, infection and wound problems, and cancer promotion or carcinogenicity.

Extrapolating from sales data, Dr. Mroz estimated that about 165,000 patients received rhBMP-2 in 2011, and 148,000 will do so this year. He estimated that two thirds of this usage is off-label. A recent survey of Spineline’s readership, for example, found that most of the responding surgeons use rhBMP-2 for various off-label fusion procedures.

The common way to obtain data about the safety and efficacy of the product is to review the literature, but Dr. Mroz noted that such a review will be based on a relatively small number of patients involved in studies, versus the large number who actually receive the product. Another consideration is the considerable heterogeneity in study design, reporting, and execution, as well as the conflict-of-interest problems outlined by Dr. Carragee.

Registries and insurance databases have great potential for following large numbers of patients, Dr. Mroz said. Theoretical merits include prospectively collected data and the ability to follow implementation of techniques and technologies in clinical practice. Such databases would also enable indications to be monitored across regions and over time and outcome comparisons to be made across regions and over time. However, he noted, such database management is complex and expensive. “The design is easy. Implementation is complex,” he said.

More transparency
Presenting an overview of the evaluation of industry-reviewed trials in the context of rhBMP-2, Kevin J. Bozic, MD, MBA, first noted that merits of industry’s involvement include its providing a source of capital, infrastructure, and risk for innovation.

“Physician-innovators, who tend to be risk-averse by nature, benefit from close collaboration with industry, which provides the capital, infrastructure, and willingness to take risk that are necessary for this type of innovation,” he said. Dr. Bozic also noted that the device industry provides much-needed support for clinical trials.

However, a number of concerns surround industry funding of clinical trials, including industry influence over selection of investigators, study design, and the dissemination of results.

Industry selection of investigators can lead to biased interpretation of results, Dr. Bozic said, noting that surgeons who receive consulting and royalty fees often have financial conflicts that may influence their objectivity in interpreting the results of a clinical trial. This issue can affect those who read manuscripts describing the results of industry-funded clinical trials, and the opinions of “thought leaders” often carry outsized influence with clinicians.

The public perception of bias is also an issue involved in industry funding, whether or not there is actually bias in the study. In terms of sharing results, Dr. Bozic noted that industry-funded research is proprietary, with no requirement for publication or dissemination. Many clinical trials that are conducted are never published; even among published trials, not all data are revealed.

Dr. Bozic chairs the Clinical Steering Committee of the Yale Open Data Access project (YODA), which is seeking to address some of the concerns with industry sponsorship of clinical research. Funded by Medtronic Inc., which manufactures the rhBMP-2 product used in the studies, the project’s stated goal is to “increase transparency and enhance the public trust in industry-funded clinical trials by facilitating the independent assessment and dissemination of data relevant to the benefits and harms of drugs and devices.”

Disclosure information: Dr. Carragee—Intrinsic Therapeutics, Simpirica; Dr. Mroz—Pearl Diver, AO Spine; Dr. Bozic: Agency for Healthcare Research and Quality, National Institutes of Health, Robert Wood Johnson Foundation, California HealthCare Foundation, Center for Health Quality and Innovation, BlueCross BlueShield Association, Integrated Healthcare Association, Pacific Business Group on Health, Ingenix, InVivo Link.