Globalization Challenges Drug Regulators

Few FDA officials discuss pharmaceutical regulation these days without reference to how the international reach of the biopharmaceutical industry has altered drug research, production, and regulation. At the annual meeting of the Food and Drug Law Institute (FDLI) in April 2014, FDA commissioner Margaret Hamburg concluded her keynote address by describing a “dramatically changing global marketplace” and its “huge implications” for FDA’s ability to ensure the safety and quality of products manufactured elsewhere. To better assess product risks, Hamburg proposed “enhanced intelligence” and more collaboration with regulatory partners through bilateral and multilateral agreements and through international organizations.

In addition to conducting more inspections and oversight of foreign manufacturers, FDA is working with international organizations to communicate its policies and standards more clearly and to enhance regulatory capacity in emerging countries. In a March 2014 lecture to the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA), Hamburg described efforts underway to form an International Coalition of Medical Regulatory Authorities (ICMRA), which would work to coordinate and enforce regulatory standards to ensure product safety and quality around the world.

At the same time, FDA and the European Medicines Agency (EMA) annouced plans to expand their many collaborative programs, including renewal of a pilot program that allows for parallel review and consultation on quality-by-design (QbD) components to new drug applications and supplements, an initiative designed to provide consistency and clarity to QbD policies.

At a London meeting in April, senior leadership from FDA, EMA, and the European Commission reviewed efforts to leverage each other’s inspection resources; collaboration to support global development of biosimilars; pediatric cluster meetings to encourage more common policies for pediatric studies and applications; information exchange by the EMA-FDA pharmacovigilance cluster; and broader cooperation related to veterinary medicines. The participants also discussed the creation of a EU-US Identification of Medicinal Products task force to explore adoption of US substances registration software in the EU, with an eye to forming a global identification system for medicinal products.

And last month, Howard Sklamberg, deputy commissioner for Global Regulatory Operations and Policy (GO), Janet Woodcock, director of the Center for Drug Evaluation and Research, and Karen Midthun, director of the Center for Biologics Evaluation and Research, unveiled a new initiative to collaborate more with EMA and European governing bodies to enhance pharmaceutical quality. FDA will be represented by a European-based team, with the aim of moving beyond information-sharing to “strengthen mutual reliance” on trusted regulators outside the US.

Challenges in India and China
At the MHRA meeting, Hamburg commented on her visit to India in February and FDA efforts to expand inspections and develop stronger ties with local regulatory authorities. The commissioner acknowledged that FDA has imposed import alerts on multiple drugs produced by leading Indian pharmaceutical companies such as Wockhardt Ltd. and Ranbaxy Laboratories, but emphasized that FDA was not “targeting” Indian manufacturers, but applying consistent inspection and quality evaluation standards to all products imported into the US.

FDA is expanding its presence in China even more to monitor the rising volume of APIs and medical products produced for US markets. At a hearing before the US-China Economic and Security Review Commission, held in Washington, D.C. in April 2014 to assess the safety of medical products imported from China and other health-related trade issues, this Congressionally appointed panel queried experts on the difficulties faced by FDA and manufacturers in ensuring the quality of Chinese drug products and components.

Christopher Hickey, the director of FDA’s China office, reported on increased FDA inspections in China—up to 84 in 2013 from 46 in 2010. Hickey acknowledged that his office has only two full-time field inspectors, but has plans to double FDA’s China staff, pending resolution of delays in obtaining necessary visas. He also noted formation of an FDA-China working group on economically motivated adulteration of medical products.

With some 4000 establishments producing medical products and substances intended for the US, however, Commission members concluded that FDA’s operation seems “woefully, inadequately staffed” for its job. Numerous API samples are falsified or substandard, according to research by the American Enterprise Institute. Alan Coukell of The Pew Charitable Trusts described rising concern over reliance on Chinese sources for key ingredients in older pain-relief medicines and antibiotics. He noted that more frequent FDA inspections of foreign drug establishments are important in prompting manufacturers to meet quality measures and agreed with Hickey that manufacturers of finished drugs need to do more to monitor suppliers and contractors.

Global outreach
While inspections and import alerts attract public attention, FDA also emphasizes its role in China and other regions in educating public officials and industry leaders on US policies and standards. Sklamberg’s GO organizes a range of capacity building programs and collaborative activities designed to strengthen regulatory systems in developing countries and to explain US and international manufacturing policies and standards to local authorities.

Similarly, leading trade and professional organizations are broadening international outreach and educational programs to support these efforts. The Parenteral Drug Association (PDA) has a European subsidiary and chapters around the world, including a new one in Singapore. These entities hold conferences and training courses on quality manufacturing and testing, as seen in a program this month on parenteral manufacturing in Istanbul.

The Drug Information Association (DIA) recently established its global headquarters in Washington, D.C. to better serve 18,000 members in 80 countries through operations in Europe, Japan, India, China, and Latin America. DIA’s chief executive, Barbara Lopez Kunz, came from Battelle with strong international management experience to oversee DIA’s worldwide growth, which will be highlighted at its 50th annual meeting this month.

The International Society of Pharmaceutical Engineers (ISPE) is unveiling a Drug Shortages Prevention Plan this month, along with plans to collaborate on a similar proposal for the EMA. ISPE and PDA are working with European associations and regulators to craft a plan that addresses shortage-related quality issues relevant to the European market.

Global expansion has been a prominent theme at the United States Pharmacopeia (USP), which now has offices and laboratories in India, China, and Brazil to provide local manufacturers with access to reference standards, test methods, and training programs on correct procedures for testing and ensuring product quality. USP’s Promoting the Quality of Medicines initiative, which is funded by the US Agency for International Development, also assists manufacturers in developing nations produce medicines that meet quality and safety standards; a recent five-year extension of the program will provide up to $75 million for USP to provide technical assistance to government regulatory systems in establishing domestic quality control laboratories, quality monitoring systems, and effective domestic regulatory authorities.

Efforts to harmonize pharmacopeial standards in different regions over several decades have been stymied by differences in legal authority and traditional practices in different countries. Pharmacopeial harmonization now is shifting to a more prospective approach, working with the World Health Organization to develop common testing practices and standards-setting processes.

These activities will be on the agenda at the next USP convention in April 2015, which will set the stage for USP programs through 2020, when the organization marks its 200th anniversary. To prepare for these and other challenges, USP’s new chief executive officer, Ron Piervincenzi, is consulting with stakeholders, reviewing the organization’s operations, and examining options for future growth and change.

About the Author
Jill Wechsler is BioPharm International's Washington editor, tel. 301.656.4634, jwechsler@advanstar.com. Read Jill’s blogs at PharmTech.com/wechsler.