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Increased pharmaceutical trade creates new challenges for regulatory oversight.
Adam Gault/Getty ImagesEmerging markets are playing an increasingly important role in the strategy of pharmaceutical companies from both a revenue and supply perspective. Attendant to that increased globalization comes additional regulatory oversight and cooperation. The author highlights recent efforts by FDA to develop greater collaborative and innovative approaches in overseeing the pharmaceutical supply chain.
The increased globalization of the pharmaceutical industry is not only reflected in the rising importance of emerging markets to pharmaceutical companies’ bottom lines, but also in the supply chain for pharmaceutical ingredients. As overall trade, including pharmaceuticals, increases between the United States and other countries, regulatory agencies are tasked with overseeing an increasingly more expansive and complex supply chain.
Challenges of globalization
“Sweeping economic and technological changes have revolutionized international trade over the last several decades, creating a truly global marketplace for goods and services,” said Steven Solomon, associate director for global operations and policy in FDA’s Office of Global Regulatory Operations and Policy, in testimony before the Congressional–Executive Commission on China in May 2013. Solomon offered input on FDA’s work in ensuring global product safety and quality and the agency’s work in China (1). To illustrate the extent of globalization, Solomon offered certain key statistics. The number of FDA-regulated shipments (includes food, drugs, and other FDA-regulated products) has more than tripled from 8 million import entry lines per year a decade ago to 28 million entry lines in fiscal year (FY) 2012. In FY 2013, entry lines are anticipated to reach 34 million. The agency tracks import shipments using entry lines, which refer to each portion of a shipment that is listed as a separate item on an entry document. “As trade increases and US consumers continue to demand global products, FDA’s ability to ensure the safety and quality of these imported products will depend on its execution of a myriad of global engagement strategies,” he said. For pharmaceuticals, approximately 40% of finished drugs in the US comes from overseas, and approximately 80% of manufacturers of APIs are located outside the US (1).
The increased trade in FDA-regulated products, including pharmaceuticals, has obliged the agency to develop more collaborative and resourceful approaches with foreign counterparts. “FDA’s success in protecting the American public depends increasingly on its ability to reach beyond US borders and engage with its government regulatory counterparts in other nations, as well as with industry and regional and international organizations, to encourage the implementation of science-based standards to ensure the quality and safety of products before they reach our country,” said Solomon in his testimony. “FDA is working with its many partners to enhance responsibility and oversight for safety and quality throughout the supply chain” (1).
To address these challenges, FDA is using a variety of engagement strategies. Solomon noted that these efforts are in line with the 2012 US National Strategy for Global Supply Chain Security, which emphasizes a layered, risk-based approach for achieving global supply-chain systems that are secure, efficient, and resilient (1, 2). In 2011, FDA also released its report, Pathway to Global Product Safety and Quality, which outlines the agency’s strategy to transform itself from a predominantly domestically focused agency to one that is engaged in the complex, globalized regulatory environment (1, 3). Solomon further outlined some of those activities as they apply to international offices, risk-based monitoring of imported products, technical cooperation and capacity building, and new laws to increase FDA’s authority.
International offices and foreign posts. FDA’s international offices and posts are designed to build partnerships with foreign counterparts by providing enhanced opportunities for cooperation and capacity building. They also are designed to expand the agency’s knowledge base and provide a platform for inspection of foreign facilities. The agency has a permanent FDA presence in 12 foreign posts in nine countries with employees located in China, India, Latin America, Europe, the Middle East, and South Africa, noted Solomon (1).
Risk-based monitoring of imported products. Solomon also pointed to FDA’s strategy of using risk-based monitoring for imported products. “While FDA does not have sufficient resources to physically inspect all imported shipments, even if we had such resources, physically inspecting all imports would be neither practical nor strategic,” said Solomon. “However, the agency electronically screens all imports using an automated risk-based system to determine if shipments meet identified criteria for physical examination or other review,” he said (1). To enhance the agency’s ability to target high-risk products, FDA developed the Predictive Risk-based Evaluation for Dynamic Import Compliance Targeting (PREDICT). PREDICT is a screening system that uses intelligence from many sources, such as intrinsic product risks, past inspection results, intelligence data, and other information that would affect shipments, to provide the entry reviewer with risk scores on every import line. PREDICT uses information sources that include FDA and US Customs and Border Protection (CBP) data as well as data collected from foreign offices, foreign regulatory counterparts, other federal agencies, and US state counterparts. It also uses risk analyses received from agreements with academic institutions and international organizations (1).
Technical cooperation and capacity building. Part of FDA’s strategy also involves engaging in regulatory cooperation with other global partners. “The capacities of governments to manage, assess, and regulate products within increasingly complex supply chains are a fundamental factor affecting product safety and efficacy,” said Solomon in his testimony (1). “FDA is working strategically with a range of countries to provide information, tools, training, and exchange programs that contribute to building or strengthening regulatory capacity of our trading partners,” he added.
Implementing new laws. Solomon also pointed to recent legislation to facilitate FDA in its efforts, most notably, the Food and Drug Administration Safety and Innovation Act (FDASIA). With the passage of FDASIA in 2012, Congress granted FDA important new authorities, reauthorized human drug and device user fees, and authorized new user fees for generic human drugs and biosimilar biologics (1). From a FDA perspective, these authorities and fees are intended to maintain a predictable and efficient review process for medical products, provide incentives for developing new antibacterial and antifungal drugs, combat drug shortages, and enhance the agency’s efforts to ensure that US consumers have more timely access to safe, high-quality, and affordable medicines.
Title VII of FDASIA focuses on improving the safety and integrity of drugs imported into and sold in the US (1). The new authority increases FDA’s ability to collect and analyze data to enable risk-informed decision-making, advance risk-based approaches to facility evaluation, partner with foreign regulatory authorities to leverage resources through information-sharing and recognition of foreign inspection, and allow the use of other tools intended to improve quality throughout the supply chain (1). In his testimony, Solomon pointed to the law’s requirement that foreign and domestic companies provide information on threats to the security of the drug-supply chain and improvements to current registration and listing information.
FDA activities in China
With increasing overall trade with China, FDA is also faced with the challenge to provide strengthened oversight for products coming from China. During FY 2007–2012, the total number of shipments of FDA-regulated products from China increased from approximately 1.3 million entry lines to 4.5 million lines. Of the 4.5 million lines arriving from China in FY 2012, 67% were drugs and medical devices, and 6% were human food products. Approximately 5% of imports into the US of drug and biologics come from China (1).
Solomon noted that FDA has 13 officers posted in three locations in China: Beijing, Shanghai, and Guangzhou. This staffing includes eight US employees and five Chinese staff. The purpose of FDA’s China office is to strengthen the safety, quality, and effectiveness of FDA-regulated products produced in China for export to the US. Solomon noted several ways in which the agency is seeking to meet that goal. These efforts include: collaborating, capacity-building, and confidence-building with Chinese regulatory counterparts at the central, provincial, and municipal level; reaching out to regulated Chinese firms that wish to export their products to the US to enhance understanding of and compliance with FDA standards; monitoring and reporting on conditions, trends, and events that could affect the safety and effectiveness of FDA-regulated products exported to the US; conducting inspections at facilities that manufacture FDA-regulated goods; and increasing the knowledge base and understanding of key stakeholders about FDA regulations and science-based approaches to strengthen product safety, quality, and effectiveness (1).
In mid-April 2013, FDA met with the China Food and Drug Administration (CFDA) in Washington, DC to discuss the collaboration between FDA and CFDA across more than a dozen topic areas. “While much of the strengthening of our relationship with CFDA has come through day-to-day collaboration between FDA’s China office and CFDA officials in Beijing, there are other significant ties in multiple areas across our agencies,” said Solomon (1). These efforts include regular meetings with a CFDA and US working group on economically motivated adulteration. It also involves collaboration by FDA and CFDA in working under the auspices of the World Health Organization’s Working Group for Member States on Substandard, Spurious, Falsely Labeled, Falsified and Counterfeit Medicines (1). Solomon also said that FDA and CFDA inspectors regularly observe one another’s inspections. Additionally, in May 2013, FDA and CFDA cohosted a workshop to enhance collaboration in addressing Internet-based, illegal distribution of adulterated drugs (1).
Solomon noted other examples as well. Between 2010 and 2012, FDA held a series of workshops on good clinical practices for Chinese inspectors who inspect sites that conduct clinical trials to support the development of pharmaceuticals. “Prior to the workshops, CFDA had few well-trained inspectors able to conduct inspections of clinical research sites,” said Solomon, in his testimony. “FDA’s training in this area helped CFDA to establish its national clinical research inspectorate. FDA regularly invites these CFDA inspectors to observe agency [FDA] clinical research inspections in China to continue to enhance CFDA’s understanding of FDA requirements” (1).
Solomon also noted that at the request of CFDA, FDA’s China Office and Office of Criminal Investigations worked with US Internet-hosting companies to shut down 16 Chinese-language websites that illegally sold unapproved medical products through servers located in the US (1). Also, in 2012, CFDA provided to FDA’s China Office a list of Chinese pharmaceutical firms against which CFDA had taken regulatory action because of their failure to comply with relevant standards for good manufacturing practices. From the list, FDA identified 61 firms that had shipped products to the US and targeted these firms as priorities for inspection (1).
1. S. Solomon, “FDA’s Activities Related to China,” testimony before the Congressional–Executive Commission on China (Washington, DC, May 22, 2013).
2. Office of the President of the United States, “National Strategy for Global Supply Chain Security (Washington DC, January 2012).
3. FDA, Pathway to Global Product Safety and Quality (Rockville, MD, July 2011).