首页 > 资讯 > 美国参议院质询 FDA 药品生产境外检查

出自识林

2020-06-05

药品供应链极其复杂，并且依赖于遍布全球的生产场地。COVID-19 大流行给这一复杂系统带来了巨大压力。同时，大流行还引发了人们对于美国药品供应对国外制造商的依赖程度的关注，并再次对FDA施加压力，要求其提高美国的药品制造能力并加强对国外制药商的审查。

在此背景下，2020年6月2日，美国参议院财政委员会就FDA对全球药品供应链的监督举行了听证会。听证会的标题为“ COVID-19及以后：对FDA国外药品生产检查程序的监督”，听证会上有来自FDA高层（包括监管事务副局长，药品审评和研究中心（CDER）监管项目副主任，以及全球政策和战略副局长），政府问责办公室（GAO）以及行业高管的证词。

为强调参议院的关切，财政委员会主席 Chuck Grassley 在听证会开幕词中指出，财政委员会有“义务”确保政府和美国纳税人花钱购买的药品“符合质量标准”。一些委员会成员还指出，药品供应链是国家安全问题。

听证会涉及与FDA和医疗卫生相关的广泛问题。以下是听证会上有关FDA对国外药品生产监督的五大要点。

1. FDA 支持自己的国外检查做法。

面对委员会成员对于FDA对国外药品生产设施监督的怀疑，FDA官员在准备好的证词和对质询的回应中对FDA的国外检查计划提出了有力辩护。尽管参议员一再对美国对国外生产的原料药（API）和制剂的依赖表示担忧，但FDA的回应表明其不太可能对检查做法或COVID-19回应措施进行重大改变。

FDA监管事务副局长Judith McMeekin指出，自2014年以来，FDA执行的国外药品设施检查数量一直超过国内药品检查数量，反映了国外药品制造的增长。

CDER监管项目副主任Douglas Throckmorton证明了FDA的监督是有效的，指出FDA主动检测了成品制剂的成分，而这些检测发现只有大约1％的药物不满足质量标准。

关于COVID-19大流行期间的药品供应链安全，Throckmorton补充表示，作为FDA大流行应对措施的一部分，FDA一直在扩展其机构间合作伙伴关系，包括与FEMA（联邦紧急事务管理局）在药品供应分配和信息共享方面合作，与HHS（卫生部）和BARDA（生物医学高级研究与开发局）在战略国家储备方面合作，以及与DEA（美国禁毒署）在有关管制物质方面合作。

FDA全球政策与战略副局长Mark Abdoo还辩护介绍了FDA开发新的执法和法规工具，加强与国外机构的合作，制定国际统一标准，就FDA要求对国外企业进行教育以及提高供应链透明度方面的工作。Abdoo提到互认协议，允许FDA依靠从某些外国监管机构获得的检查信息来减少检查工作的重复。此外，Abdoo作证表示，FDA与中国国家药品监督管理局合作，以帮助统一检查标准。

2. FDA面临增加国外突击检查的压力。

该委员会的关注点主要集中在中国和印度这两个最大的国外原料药和成品制剂供应国的生产实践和质量监督上。参议员再三批评表示，由于FDA对国外检查提供事前通知，FDA的国外检查没有国内检查那么严格。FDA面临着委员会成员的反复呼吁：通过在国外机构进行更多突击检查来“公平竞争”，并根据国外检查期间有意试图欺骗FDA调查人员的报告，采取更多措施维护FDA检查的完整性。

FDA官员作证表示，FDA对国外药品生产设施执行事先通知的检查和突击检查。McMeekin承认“大多数国外检查都是提前通知的”，但她解释指出，通常必须提前通知，以确认场地进行的活动属于FDA管辖范围之内，并确保人员和记录的可得。此外，McMeekin指出，由于FDA的法定检查授权21 USC 374不适用于国外设施，因此使用提前通知以确保允许FDA执行检查。

GAO医疗卫生主管Mary Denigan-Macauley对FDA在进行国外检查之前提供长达三个月的通知并依赖国外设施人员翻译关键文件表示担忧。此外，Denigan-Macauley表示，尽管FDA近年来在国外执行了更多检查，但许多国外药品生产设施从未得到过检查。Denigan-Macauley最后作证指出，FDA的国外检查对确保美国的药品质量“绝对至关重要”。

一些提问突出了对FDA提前通知的检查，以及不愿增加突击检查的担忧。当被问及FDA为什么终止了FDA在印度增加突击检查的“试点计划”时，Abdoo回答说，该计划本质上总会受到限制的，但是 FDA 利用了所获得的经验来加强国外检查计划。McMeekin 还指出，在大流行之前，FDA仍在中国和印度执行突击检查，但重点是在有因检查上。

FDA并没有承诺改变其提前通知的做法，但是由于国会及其他方面的压力，国外机构将来可能会发现包括常规检查在内的突击检查会有所增加。

3. FDA认为“替代工具”足以确保COVID-19大流行期间国外生产的药品质量。

在回答有关FDA COVID-19 应对的问题时，FDA官员们强调，尽管FDA无限期暂停常规的国外检查，但FDA已采取确保国外生产药品的安全性和质量的措施。这些措施包括：

• 拒绝不安全的产品进入美国；
• 在美国边境增加物理检查，其中可能包括产品抽样；
• 审查国外生产商以前的合规历史；
• 通过互认利用国外政府的信息共享；以及
• 在“提前于或代替”现场药品检查，直接向制药商索取记录。

FDA还表示将继续与美国海关和边境保护局合作，寻找违反FDCA（联邦食品药品和化妆品法案）和适用法规的受FDA监管的产品。通过这样做，在COVID-19爆发期间，FDA正依靠其法定授权拒绝进口任何“显示出”违反FDCA或实施性法规的受FDA监管的产品，并将在必要时调整由FDA进口筛查工具（PREDICT）生成的风险评分。事实上，这导致了对高风险地区产品的物理检查和抽样的增加。

尽管FDA拒绝对当前计划做出重大更改，但随着COVID-19相关中断的继续，FDA最终可能会采取其它措施来核实国外设施的合规性。对于那些传统上在FDA批准相关药品申请之前需要进行现场批准前检查的国外生产工厂，以及那些目前处于合规保留状态并等待FDA重新检查以许可现场的工厂尤其如此。

4. FDA没有提供迹象显示何时恢复国际药品检查。

参议员在其声明和问题中表达了美国对外国生产的原料药和成品制剂的依赖会对国家安全构成威胁的关切。议员们向FDA施加压力，要求其恢复国外药品设施检查。

对此，McMeekin 表示，FDA拒绝危害公共安全或其工作人员的安全，并指出，国外检查和新型冠状病毒带来了独特的挑战，包括雇用符合资质的人员。McMeekin作证表示，FDA一直致力于国际港口和邮件管理部门的执法工作，并且FDA还增加了调查在线销售的人员。FDA没有就何时恢复国外药品检查提供具体目标或估计。

5. 明确要求更多的国内药品生产以及解决药品短缺问题。

参议员们在与COVID-19相关的药品供应中断的前景展望中重新关注了两个经年历久的问题：防止药品短缺和增加美国药品生产。FDA官员表示，减少药品短缺一直是FDA长期以来的优先事项，并指出增加国内产能的方法可以作为解决方案的一部分。Throckmorton引用了FDA 2019年10月的药物短缺报告，该报告审查了造成药物短缺的根本因素，并针对这些问题提出了建议的解决方案。【FDA 发布药品短缺根本原因与解决方案报告，能否真正解决问题？】

Throckmorton强调指出，解决此问题的一种方法是增加整个药品供应链的质量管理透明度，包括建立质量评级系统。他指出，允许制药商宣传其质量评级可能会导致来自评级高、质量高的药品的溢价定价，从而增加了公司投资质量的动机。FDA之前曾指出，质量成熟度是药物短缺的准确预测指标。因此，对高质量生产采取基于市场的激励措施，可以通过吸引更多制药商并减少与质量相关的供应链中断来减少药品短缺。从理论上讲，这样的系统可以使高质量的国内制造业在经济上更具吸引力。

Throckmorton补充指出，美国在“先进制造”方面的优势可能会提供一种以解决药品短缺问题为基础的构建国内制造能力的机会。

英文原文

Five key takeaways from the Senate hearing on FDA oversight of foreign drug manufacturing

The pharmaceutical supply chain is extremely complex and relies on manufacturing sites located throughout the world. The COVID-19 pandemic has placed significant strain on this complex system. It has also drawn attention to the extent to which the U.S. drug supply relies on foreign manufacturers, and renewed pressure on FDA to promote U.S. drug manufacturing capacity and increase scrutiny of foreign drug manufacturers.

Against this backdrop, on June 2, 2020, the U.S. Senate Committee on Finance held a hearing on FDA’s oversight of the global pharmaceutical supply chain. The hearing, entitled “COVID-19 and Beyond: Oversight of the FDA’s Foreign Drug Manufacturing Inspection Process,” included testimony from FDA senior leadership, including the Associate Commissioner for Regulatory Affairs, the Center for Drug Evaluation and Research’s (CDER) Deputy Director for Regulatory Programs, and the Associate Commissioner for Global Policy and Strategy, the Government Accountability Office (GAO), and industry executives.

Underscoring the Senate’s concerns, Chairman Chuck Grassley opened the hearing by noting that the Committee on Finance has an “obligation” to ensure that drugs paid for by the government and U.S. taxpayers “satisfy quality standards.” Several of committee members also noted that the pharmaceutical supply chain is a national security issue.

The hearing covered a broad array of FDA and health care related issues. Below are five key takeaways from the hearing regarding FDA's oversight of foreign drug manufacturing.

1. FDA stands behind the agency's foreign inspection practices

In the face of committee member skepticism about FDA’s oversight of foreign drug manufacturing facilities, FDA officials presented a strong defense of the agency’s foreign inspection program in prepared testimony and in response to questioning. While senators raised repeated concerns about U.S. reliance on foreign-manufactured active pharmaceutical ingredients (API) and finished drug products, the FDA response indicated that the agency was not likely to pursue major changes to inspectional practices or COVID-19 response measures.

Judith McMeekin, FDA Associate Commissioner for Regulatory Affairs, noted that since 2014, FDA has consistently performed more foreign drug facility inspections than domestic, reflecting the growth of foreign manufacturing.

CDER Deputy Director for Regulatory Programs, Douglas Throckmorton, testified that the agency’s oversight was effective, noting that FDA proactively tests finished pharmaceutical ingredients, and those tests find only about 1% of drugs fail to meet quality standards.

With respect to drug supply chain security during the COVID-19 pandemic, Throckmorton added that FDA has been expanding its interagency partnerships as part of the agency’s pandemic response, including collaborating with FEMA regarding drug supply distribution and information sharing, HHS and BARDA regarding the Strategic National Stockpile, and DEA regarding controlled substances.

FDA Associate Commissioner for Global Policy and Strategy Mark Abdoo also defended the agency’s work to develop new enforcement and regulatory tools, increase collaboration with foreign bodies, craft internationally harmonized standards, educate foreign industries about FDA requirements, and increase transparency in the supply chain. Abdoo cited the Mutual Recognition Agreement as permitting FDA to rely on inspectional information obtained from certain foreign countries to reduce duplication of inspection efforts. In addition, Abdoo testified that FDA coordinates with China’s National Medical Products Administration to help unify inspections standards.

2. FDA is under pressure to increase unannounced foreign inspections

The committee’s concerns largely centered on manufacturing practices and quality oversight in China and India, the largest foreign suppliers of API and finished drug products. Senators repeated criticism that the agency’s foreign inspections are less stringent than domestic inspections due to FDA’s practice of providing advance notice of foreign inspections. FDA faced renewed calls to “level the playing field” by performing more unannounced inspections at foreign facilities and to do more to maintain the integrity of FDA inspections in light of reports of intentional attempts to deceive FDA investigators during foreign inspections.

FDA officials testified that the agency conducts both announced and unannounced inspections of foreign drug manufacturing facilities. McMeekin acknowledged that “most foreign inspections are preannounced” but explained that preannouncements are often necessary to verify that a site is performing activities that fall within FDA’s jurisdiction and to ensure the availability of personnel and records. In addition, McMeekin noted that because FDA’s statutory inspectional authority, 21 USC 374, does not apply to foreign facilities, preannouncement is used to ensure FDA will be permitted to conduct the inspection.

GAO health care director Mary Denigan-Macauley expressed concerns that FDA provides up to three months’ notice prior to foreign inspections and relies on foreign personnel to translate key documents. In addition, Denigan-Macauley stated that although FDA is conducting more inspections overseas in recent years, many foreign drug manufacturing facilities have never been inspected. Denigan-Macauley concluded by testifying that FDA's foreign inspections are “absolutely critical” to ensuring drug quality in the U.S.

Several questions highlighted concerns about FDA’s preannouncement of inspections and reluctance to increase unannounced inspections. Asked about why FDA ended an agency “pilot program” of increased unannounced inspections in India, Abdoo responded that the program was always meant to be limited in nature but that the agency used the experience to strengthen the foreign inspection program. McMeekin also pointed out that prior to the pandemic, FDA was still conducting unannounced inspections in China and India, but with a focus on for-cause inspections.

FDA did not commit to changing its practices on advanced notice, but given the pressure from Congress and beyond, foreign facilities may see an increase in unannounced inspections, including for routine inspections, in the future.

3. FDA believes “alternative tools” are adequate to ensure the quality of foreign manufactured drugs during the COVID-19 pandemic

In response to questions regarding the agency’s COVID-19 response, FDA officials highlighted measures already taken to ensure safety and quality of foreign manufactured drugs despite FDA’s indefinite suspension of routine foreign inspections. These include:

• Denying entry of unsafe products in to the U.S.;
• Increasing physical examination at the U.S. border, which may include product sampling;
• Reviewing a foreign manufacturer’s previous compliance history;
• Utilizing information sharing from foreign governments through mutual recognition; and
• Requesting records directly from manufacturers “in advance of or in lieu of” on-site drug inspections.

FDA also stated that it will continue its work with U.S. Customs and Border Protection to seek out FDA-regulated products that are in violation of the FDCA and applicable regulations. In doing so, FDA is relying on its authority to refuse the importation of any FDA-regulated products that “appear” to violate the FDCA or its implementing regulations, and will adjust risk scores generated by the agency’s import screening tool (PREDICT), as necessary during the COVID-19 outbreak. In practice, this has led to increased physical examination and sampling of products from high-risk areas.

Although FDA has resisted making significant changes to its current program, the agency may ultimately implement additional measures to verify foreign facility compliance as COVID-19 related disruptions continue. This is particularly true for foreign manufacturing sites that would traditionally require an on-site pre-approval inspection prior to FDA approving a relevant drug application, as well as those sites currently on a compliance hold and awaiting FDA re-inspection to clear the site.

4. FDA offered no indication as to when it will resume international drug inspections

In their statements and questions, Senators expressed concerns that U.S. reliance on foreign-manufactured API and finished drug products posed a risk to national security. And lawmakers applied pressure on FDA to resume foreign drug facility inspections.

In response, McMeekin stated that the agency refused to jeopardize public safety or that of its staff, noting that foreign inspections and the novel coronavirus present unique challenges, including the hiring of qualified personnel. McMeekin testified that FDA has been continuing to focus on enforcement efforts at international ports and mail authorities, and the agency has additional staff investigating online sales. No specific target or estimate was provided by FDA as to when it would resume its foreign drug inspections.

5. There is a clear push for more domestic drug manufacturing and solutions to drug shortages

Senators used the prospect of COVID-19-related drug supply disruptions to renew attention to two perennial issues: preventing drug shortages and increasing U.S. drug manufacturing. FDA officials said reducing drug shortages has been a longstanding agency priority and noted ways in which increased domestic capacity could be part of the solution. Throckmorton cited FDA’s October 2019 drug shortages report, which examined the underlying factors responsible for drug shortages and recommended solutions for these problems; we summarized the agency’s actions in this arena online here and here.

Throckmorton emphasized that one way to address this issue would be to improve quality management transparency throughout the pharmaceutical supply chain, including establishment of a quality rating system. He stated that allowing manufacturers to advertise their quality rating could result in premium pricing for drugs from highly rated, high-quality sources, increasing incentives for companies to invest in quality. FDA has previously stated that quality maturity is an accurate predictor of drug shortages. Accordingly, introducing market-based incentives for high-quality manufacturing could reduce drug shortages by attracting more manufacturers and reducing quality-related supply chain interruptions. Such a system could, in theory, make high-quality domestic manufacturing more economically attractive.

Throckmorton added that the U.S. advantage in “advanced manufacturing” could provide an opportunity to build out domestic manufacturing capabilities in a way that also addresses drug shortage issues.

作者：Hogan Lovells 律所 Jim Johnson, Scott Kaplan, Christopher Fanelli
编译：识林-椒
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