Ensuring Pharmaceutical Quality Through International Engagement

By: Howard Sklamberg, J.D.

As we’ve written and spoken so much about, the FDA has had to transform itself from a domestically-focused regulatory agency into a 21st century global health organization.  This transformation has come in the face of economic and technological changes that have revolutionized how we carry out our mission. We live in a world where other countries increasingly produce—at least in part—the food and medical products our consumers and patients use in their daily lives.

Howard SklambergProducts the FDA regulates now come from more than 150 countries—many with much less sophisticated regulatory systems than our own. In this international marketplace, 40 percent of our finished drugs are imported, and approximately 80 percent of the manufacturers of active pharmaceutical ingredients used in the United States are located outside our borders.

Ensuring the quality of products in a global environment is a tall order. At every stage in the production of pharmaceutical products, and all along the global supply chain, things can go wrong.  Products can be improperly formulated, manufactured, or packaged. They can be contaminated or counterfeited. And the challenges are multiplied when the supply chain stretches around the world.

FDA is on the ground, around the world, inspecting facilities, developing relationships and providing advice.

But securing the global supply chain requires more than that. It calls for a cooperative and worldwide endeavor. It means working with our regulatory counterparts abroad to build capacity. It means harmonizing our standards for the sake of safer products and greater efficiency. It means engaging with industry and with regional and international organizations.

The Food and Drug Administration Safety and Innovation Act (FDASIA), which Congress enacted in 2012, included some important provisions designed to improve the safety and integrity of imported drugs sold in the United States. Some of the provisions are focused on FDA’s inspectional activities overseas. For example, FDASIA increases FDA’s ability to partner with foreign regulatory authorities to leverage resources through increased information-sharing and recognition of foreign inspections.

We now have more than 60 agreements with foreign counterparts to share certain information in inspection reports and other non-public information that can help us make better decisions about the safety of foreign products.

This type of collaboration not only increases our ability to evaluate pharmaceutical facilities, but allows experts to learn from each other. The result: an outcome whose sum total exceeds its individual parts.

That is exactly why today we announced an initiative to expand on our existing work to ensure that the public has access to quality pharmaceuticals. Through this initiative, and in cooperation with the European Commission (EC) and the European Medicines Agency (EMA), FDA will aim to deepen our reliance on trusted regulators outside of the U.S. who provide equivalent public safety and quality protection.

This mutual reliance initiative builds on our existing relationships with the EC, the EMA, and member states of the European Union. Under this new initiative, the goal is to increase our exchange, with the EC and the EMA, of information that is critical to making decisions that protect the public health. And together we will be more efficient and effective in targeting our resources for inspecting pharmaceutical operations.

This is the latest step in our continuing efforts to improve the quality of pharmaceutical products – a step that will deploy a dedicated FDA team to work with our European counterparts on a host of issues. The team, which will focus full time on pharmaceutical quality, will include experts from our Center for Biologics Evaluation and Research, our Center for Drug Evaluation and Research, and our Office of Global Regulatory Operations and Policy.

As a public health regulatory agency with a global presence, we look forward to strengthening our mutual reliance and capitalizing on our shared interests. The initiative we embraced today signals yet another important step forward for pharmaceutical quality here in the U.S.—and around the world.

Howard Sklamberg, J.D., is FDA’s Deputy Commissioner for Global Regulatory Operations and Policy

FDA Confers with International Counterparts to Advance Regulatory Science

By: Margaret A. Hamburg, M.D.

I have recently returned from the 8th International Summit of Heads of Medicines Regulatory Agencies, which was hosted on December 3-6, 2013, by the Netherlands’ Medicines Evaluation Board in Amsterdam. These annual meetings are an important forum for the exchange of information, views and regulatory strategies among the chief executives of major and like-minded medicines regulatory agencies. I was particularly pleased to be able to contribute to these discussions as a speaker on a panel on regulatory science together with Dr. Tatsuya Konda, M.D., Ph.D., the chief executive of Japan’s Pharmaceuticals and Medical Devices Agency.

Margaret Hamburg, M.D.The theme of this year’s summit was “Changes in the Regulatory Landscape,” and my foreign colleagues and I had plenty to talk about. Overcoming the challenges and reaping the benefits of regulatory science is even more critical today, when the FDA and other regulatory agencies face new and growing tasks in the global marketplace. All of us have to contend with the huge changes in the size and nature of international trade caused by emerging markets, developing economies, and increased cross-border flows of goods, information and capital.

As regulators, my international counterparts and I have many issues in common. They include the increasing complexity of new drug products and drug development; growing geographic distribution of markets; greater demands for public accountability and transparency in our work; budgetary and political challenges to regulatory oversight; and, the overriding need to keep up with the rapid changes in science and technology. Given these shared concerns, building cross-border partnerships and finding common solutions is paramount.

I reiterated to the conference our goal to encourage and strengthen cooperation and collaboration among those nations that are actively working to advance regulatory science. Regulatory science endeavors to use current and emerging knowledge to create new tools, standards and approaches for reliable assessment of the safety, effectiveness, quality and performance of medical products. At its best, this process is based on findings, evaluations, discussions and collaboration by scientists throughout the world.  And it is meetings like the recent summit in Amsterdam that help enhance this cooperation and the development of strategies that promote and strengthen the understanding, acceptance and application of regulatory science.

As the FDA embraces its international role in today’s complex regulatory environment, we fully accept the need to think and act globally more than ever before. I look forward to working with other nations’ regulators, the academic community, non-governmental organizations and industry as we join forces to advance regulatory science, the road to even better protection and advancement of the public health.

Margaret A. Hamburg, M.D., is the Commissioner of the Food and Drug Administration

New Law Enhances Safety of Compounded Drugs and Protection of the Drug Supply Chain

By: Margaret A. Hamburg, M.D.

Since last year’s tragic meningitis outbreak and subsequent events involving compounded drugs, Congress has been hard at work to pass new legislation to provide FDA with the appropriate authorities for regulating compounded drugs to help make these products safe for the American public.

Margaret Hamburg, M.D.Over a much longer period of time, efforts have been made in Congress to enhance the security of the drug supply chain and protect consumers from exposure to counterfeit, stolen, contaminated or otherwise harmful drugs.

I am pleased that the Drug Quality and Security Act can help FDA protect public health in both of these critical areas.

One part of the new law offers a step forward in FDA’s oversight of certain entities that prepare compounded drugs. The new law will enable these compounders to register with the FDA to become “outsourcing facilities,” making them subject to certain other requirements including Federal quality standards, known as current good manufacturing practice. These facilities will also be subject to inspection by FDA on a risk-based schedule. If compounders register with FDA as outsourcers, hospitals and other health care providers will be able to provide their patients with drugs that were compounded in facilities that are subject to FDA oversight and federal requirements for current good manufacturing practice, among others. To that end, we will be encouraging healthcare providers and health networks to consider purchasing compounded products from facilities that are registered with FDA and subject to risk based inspections.

Drugs produced by compounders that are not registered as outsourcing facilities must meet certain other conditions described in the law, or they will be regulated by FDA as conventional drug manufacturers.

Generally, the state boards of pharmacy will continue to have primary responsibility for the day-to-day oversight of state licensed pharmacies, including traditional pharmacy compounding. And FDA will continue to cooperate with state authorities to address pharmacy compounding activities that may be in violation of the Federal Food Drug and Cosmetic Act.

Another part of the new law enables certain prescription drugs to be traced as they move through the U.S. drug supply chain. The goal is to protect the public from exposure to counterfeit, stolen, or otherwise harmful drugs. This will require manufacturers, repackagers, wholesale drug distributors, and dispensers (other than most licensed health care practitioners) to provide product and transaction information with each sale and notify the FDA and other stakeholders of illegitimate products, which will result in improved detection and removal of potentially dangerous drugs from the supply chain.

Starting four years after enactment of the law, manufacturers, followed by repackagers, will be required to affix a unique product identifier to each drug package that contains the drug’s national drug code (NDC), serial number, lot number, and expiration date. Starting six years after enactment of the law, wholesale drug distributors, followed by dispensers, may only trade products that  are encoded with product identifiers and will be able to verify the product identifier if they determine that they have  suspect product. Ten years after enactment, supply chain stakeholders and FDA will benefit from an electronic, interoperable system which will facilitate the efficient exchange of product and transaction information for prescription drugs at the individual package level. The system, when fully implemented, will enable verification of the legitimacy of the drug product identifier down to the package level, enhanced detection and notification of illegitimate product, and improved efficiency of recalls.

The Drug Quality and Security Act is a significant step toward having new and stronger drug quality and safety laws. While the law does not provide FDA with all the additional authorities sought, these provisions are a sign of progress.

We are committed and prepared to implement the new law that will help us to further protect public health.

Margaret A. Hamburg, M.D., is the Commissioner of the Food and Drug Administration

Quick Look at FDA’s Mexico Post and Our Global Work

By Phyllis J. Marquitz, M.Sc., J.D.

En Español

Food is something that we all have in common. It brings people together across cultures, borders and tables. Today, about 49 percent of fresh fruits, 21 percent of fresh vegetables and 85 percent of seafood eaten in the United States are imported. Many of these products originate from Mexico, and the volume of imported goods is increasing.

Plate of musselsIndeed, Mexico ranks second only to Canada as the largest agricultural trading partner with the United States with bilateral trade of over $20 billion, according to the U.S. Department of Agriculture. The ever-increasing imports of food are reshaping the way FDA does business, and the task of ensuring that food is safe and of high quality for American consumers no longer begins or ends at the border.

One important step FDA has taken to ensure the quality of food is to move some of our operations beyond our borders, opening 13 offices in other parts of the world since 2009. The office in Mexico opened in 2010 and is located in the capital, Mexico City, the largest city and most important cultural, educational and financial center.  Our five-person office, which includes one other FDA staffer plus three local employees, is part of the agency’s regional Latin American Office, with posts in Costa Rica and Chile.

Part of what we do is educate industry groups and academia about FDA’s public health regulations so that firms will have the tools they need to implement preventive measures that will help ensure that products are safe throughout the supply chain. In this year alone, our Mexico City office organized 20 outreach events that drew over 1,000 representatives from industry, universities and local governments.

A key part of our job is to help implement existing international arrangements between the United States and Mexico and other foreign governments. These arrangements facilitate and help ensure high quality standards we expect and insist on before any food, drug, or other health care product can be imported into the United States.

To help maintain preventive controls and science-based standards and enable swift regulatory action, we conduct outreach activities, translate documents and exchange strategic, scientific, and regulatory information routinely with our Mexican counterparts. They include the Mexican Federal Commission for Protection for Sanitary Risks, known as COFEPRIS. A recent example was the case of a non-compliant dietary supplement that contained active pharmaceutical ingredients. COFEPRIS acted on FDA’s information by conducting its own product analysis and stopped manufacturing of a product that might otherwise have entered the United States.

We’ve also sponsored pilot projects with Mexican counterparts to increase our knowledge base around the inspection systems in both countries. We need to know specifically how preventative systems work in day-to-day production and how Mexico enforces its regulations to ensure product safety and quality.

Partnerships with regulatory counterparts are also part of FDA’s efforts to protect public health. An example is an FDA Statement of Cooperation with COFEPRIS, signed in June 2012. This arrangement demonstrates a strong commitment at all levels of the U.S. and Mexican Governments to work together on food safety under a recent Food Safety Cooperative Arrangement, signed by the U.S. Secretaries of USDA and the Department of Health and Human Services (FDA’s parent department) and their Mexican counterparts in May 2012 in Geneva, Switzerland.

With the FDA-COFEPRIS arrangement, FDA recognizes that COFEPRIS, through the Mexican Shellfish Sanitation Program (MSSP), has an effective molluscan shellfish sanitary control system in place. FDA and COFEPRIS will oversee continued compliance with the U.S. National Shellfish Sanitation Program requirements through jointly conducted audits of the MSSP. These audits include checking water quality and production standards at the source.

FDA continues to work with its international counterparts and partners to help ensure that safe, nutritious food is produced world-wide – before it is made available to U.S. consumers.

Phyllis Marquitz, is Assistant Regional Director for Latin America (Mexico City) within FDA’s Office of International Programs, Office of Global Regulatory Operations and Policy

FDA Voice Interviews Jesse Goodman, M.D., M.P.H., on the DARPA and NIH Project Collaboration: Human on a Chip

FDA Voice: FDA has embarked on an exciting collaboration with the Defense Advanced Research Projects Agency (DARPA) and NIH—to develop a groundbreaking tool that could help bring new treatments to patients faster, more cheaply, and more safely. Can you talk about this new technology?

Dr. Goodman:  Yes, it’s what we’re calling Human on a Chip. This is an ambitious project to create a tool that could revolutionize toxicology testing and it’s something I’m really excited to talk about.  Scientists have relied largely on animal studies to determine if a drug is toxic before testing it in humans.  And while animal testing is useful, it’s also expensive, time consuming, and has drawbacks. For example, it doesn’t always detect toxic effects specific to humans and doesn’t usually provide information about the role that genetic differences within human populations play in toxicity. It can also generate false alarms, showing an effect in animals that doesn’t predict an actual effect in people, which leads us to abandon promising new drugs. FDA is collaborating with DARPA, NIH, and the scientific community to spur innovation in this field by exploring how tools like Human on a Chip can be integrated into our development tool box to improve testing for toxicity and potentially reduce the need for animal testing.

FDA Voice:  Can you describe Human on a Chip?

Dr. Goodman: Researchers are developing microsystems using human cells to test the effects of drugs or other substances. For example, scientists have developed a micro machine chip with human lung cells that grow on a surface to form a lung-like tissue that has both air spaces and blood circulation. FDA is supporting the coupling of this chip to a heart-like chip that beats and pumps blood. We can use this type of system to evaluate, with human cells, how specialized organs like the lung and heart react to a specific chemical.

The Human on a Chip builds on this approach. FDA’s collaboration with NIH and DARPA aims to create a 3D representation of 10 different human organ systems that mimic the processes and activities of those systems, potentially linking them to form a system with major features of human biology. For instance, in a living human, the interactions of heart, lung, kidney, and liver are crucial in the functioning of all 4 organs, and all are common targets of toxicity. A tool that creates and links organ-like systems will enable scientists to observe a substance’s effects on several interacting systems simultaneously. This can make it possible to test for beneficial effects as well as for toxicity.

Once these systems are refined, if successful, they could not only improve testing beyond currently available tools, but could also be engineered to mimic disease states or be implanted with cells with a specific genetic background that is involved in specific diseases or drug interactions.

FDA Voice:  Why transform toxicology testing?

Dr. Goodman: Toxicity has been a major challenge in medical product development and in assessing environmental hazards. Technologies like Human on a Chip could help shrink the time frame it takes for new treatments to move to human testing and approval. These new tools can help identify toxicity earlier in product development, thus protecting patients, lowering development costs, and speeding new treatments to patients in need.

Human on a Chip could also contribute to developing medical countermeasures because the diseases and conditions we might need to treat in a public health emergency—like anthrax, smallpox, pandemic influenza, and radiation and toxin exposure—rarely occur naturally, often making animal models the only available tools for evaluating a new treatment’s effectiveness.

FDA Voice:  What makes FDA essential to this collaboration?

Dr. Goodman:  Our FDA scientists have vast experience using available tools to make tough scientific decisions about the safety and effectiveness of a multitude of products. They’ve seen what works and what doesn’t, and thus can provide insights and help solve challenges in defining how best to develop and evaluate new tools. Before accepting a new tool for use, FDA scientists must have the needed scientific data on how it performs to ensure that it is as safe and effective as possible. Once FDA accepts a scientific tool, industry can use it for its qualified purpose during product development.

FDA Voice:  In what other ways has FDA worked to drive innovation in toxicology testing?

Through the Critical Path and Advancing Regulatory Science initiatives, we are working to harness the use of new science and technology to transform regulatory science and help get needed products to people quickly and safely. FDA identified transforming toxicology as one of the eight priority areas where collaborative regulatory science research is essential and offers huge opportunities. In addition to Human on a Chip, FDA is collaborating with other Federal agencies, academia, and industry to bring new science to toxicology, such as on the cell-based Tox-21 project with EPA and NIH, and on FDA grants to evaluate cell-based approaches to evaluate risks of reproductive and developmental toxicity.

My office has also formed a new FDA-wide council, together with scientists from across the agency, to explore, promote, and coordinate efforts concerning chemical and toxicology-related issues. FDA’s partnership throughout the development and evaluation cycle is critical to ensuring that exciting new tools and approaches like Human on a chip speed the delivery of safe and effective new treatments to people who need them.

Jesse L. Goodman, M.D., M.P.H., is FDA’s Chief Scientist and Deputy Commissioner for Science and Public Health

Collaboration for a Global Product Safety Net

By: Mary Lou Valdez

If it takes a village to raise a child, in today’s economy it takes the support and commitment of a global community to ensure the safety of the food we eat and the medications we rely on.

This point was made clear in an Institute of Medicine report released on April 4. The report was commissioned by the FDA as the agency addresses the challenges of global supply chains, international trade, and foreign sourcing of foods, feeds, and medical products. It complements the FDA Commissioner’s Report on Global Pathway to Product Safety and Quality released last summer.

Mary Lou ValdezImports of food and drug products regulated by FDA have increased by more than 13 percent per year since 2002, resulting in a four-fold increase of products produced outside of the United States. Approximately 50% of the fresh fruits and 20% of fresh vegetables, as well as 80% of seafood consumed in America comes from abroad. Similarly, more than 80 percent of the active pharmaceutical ingredients used to make medicines are imported. To ensure that the vast array of products Americans depend on are safe, FDA focus can no longer be solely domestic – it must be global.

Since many of the products imported are from emerging and developing countries, the FDA asked the IOM to take a look at the regulatory systems in those countries to identify major gaps and to design a strategy for how the FDA, along with other regulators and stakeholders, can help to strengthen their regulatory systems and build capacity.

Not surprisingly, the IOM found that the hurdles are great in some countries where there is inadequate clean water, electricity, transportation, communication systems and Internet access. Their regulatory agencies often operate with a skeletal staff, outdated equipment and limited or non-existent surveillance systems. In some of the least resourced countries there are weak or no laws governing product safety while product safety is not a high priority in others.

The IOM Committee’s strategy was to focus on the nexus of public health, product safety, development and trade, while recognizing that regulatory systems play an important role. The IOM identifies several core elements of a regulatory system: they must be responsive, outcome-oriented, predictable, risk-based or proportionate and independent. Other important commonalities include an enterprise risk management approach to regulation; focus on securing the entire supply chain; develop a profession of regulators – an “esprit de corps”; and make accountability an essential element of their system. The IOM also acknowledges that industry must play a role in ensuring the safety of its imported products.

To help build regulatory capacity, the IOM recommends that the FDA, other federal agencies and international organizations provide technical expertise, training and tools to strengthen the surveillance system in developing countries.

We take pride in the efforts FDA already has undertaken to support and collaborate with regulatory systems across the globe, such as our foreign training programs on good clinical practice inspections and low acid canned food inspections; a medical products information “hub” for the Americas in collaboration with the Pan American Health Organization; our interagency agreements with the US Agency for International Development to better understand pharmacovigilance systems in Africa and Asia; and our involvement with the World Bank’s Global Food Safety Fund, a partnership of public and private organizations intended to boost food safety capacity around the world. And this is only a short list of our activities.

We welcome the IOM’s call to international and intergovernmental organizations to invest more in strengthening the capacity of regulatory systems in developing countries, and to track progress as a priority of development banks, regional economic communities and public health institutions.

We were pleased that the IOM supports the agency’s risk-based strategy for monitoring and inspecting imported products and recommends that the agency extend this approach by working with strong regulators in other countries to plan inspections and pool data.

However, additional legal authorities would be helpful to accomplish this goal. FDA currently is barred from sharing certain non-public information with other regulatory agencies that might lead to timely identification, prevention, and resolution of emerging threats. Nor do we have the authority to use foreign audit data collected by our foreign regulatory counterparts with strong regulatory systems that would better leverage our limited resources.

Other authorities would be helpful to help us better manage risks. These include the ability to refuse admission of a product if inspection of the manufacturing facility is delayed, limited, or denied; and allow FDA to destroy the low value but large number of unsafe drugs that are coming into the country through international mail, typically purchased over the internet. In order to enhance our risk data, we would like additional information such as unique facility identifier as a condition of registration and import that would make it easier for FDA to properly follow a threat through the supply chain.

To ensure that industry assumes appropriate responsibility for their imported product, it would be helpful for manufacturers to account for the quality and origins of the materials that go into their products and require that manufacturers provide complete information to FDA on threats to the drug supply chain. Furthermore, the use of accredited third parties that meet prescribed standards could provide an additional set of eyes to help ensure the safety of the drug supply chain.

Ensuring the safety of imported food and medicines takes all countries working together, including governments, industry, academia, and other stakeholders. But marshalling the forces of this vast community may not be enough to provide the robust regulatory system we need in today’s global marketplace without new authorities to protect the health of the American public.

Mary Lou Valdez is FDA’s Associate Commissioner for International Programs and Director, Office of International Programs