The history of the US Food and Drug Administration is marked by significant revisions in its rules and policies in response to major crises in drug, food, and vaccine safety. Now, a surge in overseas production of FDA-regulated products is driving major changes in how the agency does business. Deaths due to adulterated heparin from China in 2008 jolted the regulators into action. FDA ramped up foreign inspections and opened its first foreign offices.
That crisis, along with evidence of economically motivated drug adulteration, widespread drug counterfeiting, and extended supply chains that aggravated drug shortages at home, prompted FDA to recognize the need for further changes in agency operations. FDA Commissioner Margaret Hamburg responded by issuing a special report last year on the "Pathway to Global Product Safety and Quality" that outlines four main strategies for fundamentally revising FDA's approach to ensuring product safety and quality in a world of international outsourcing and soaring imports. The subsequent report on "Global Engagement" describes more specifically how FDA will seek to regulate food, drugs, and medical products through international collaboration and information sharing.
These documents reflect the reality that FDA will never have the resources to inspect every foreign producer of food and medical products or to monitor the growing volume of products crossing US borders. Thus, FDA officials seek to work more closely with their regulatory counterparts to reduce redundant plant inspections and extend regulatory oversight.
In addition, Hamburg restructured FDA's leadership last year by creating four overarching directorates to manage main program areas. These directorates include the new Office of Global Regulatory Operations and Policy, headed by Deputy Commissioner Deborah Autor. She is in charge of FDA's Office of International Programs (OIP), which manages the agency's foreign offices and deals with international trade, policy and regulatory issues, and the Office of Regulatory Affairs (ORA), which operates FDA's 4400-person field force that inspects manufacturers, clinical researchers, and food producers in the US and overseas.
An attorney who has been a litigator in the Department of Justice and previously headed the Office of Compliance in FDA's Center for Drug Evaluation and Research, Autor is well positioned to take on the challenge of transforming FDA into a more data-driven, strategic, collaborative operation. She understands the pressures and incentives on biopharmaceutical manufacturers striving to adjust to the global economy, and told BioPharm International Washington Editor Jill Wechsler in a recent interview that industry must do more to ensure the quality and safety of its products.
BioPharm: Why is it necessary to transform FDA to reflect global developments, and how will the agency accomplish this?
Autor: I think the starting point is to recognize how much the world has really changed and how much globalization has fundamentally changed trade, the economy, and FDA's responsibilities. For example, imports of FDA regulated products have quadrupled over the course of a 10-year period, rising from 6 million to 24 million import lines. We now regulate products from hundreds of thousands of facilities in over 150 different countries. We import 10–15% of all food consumed in the US, 40% of finished drugs, 80% of active ingredients, and half of all medical devices.
So that fundamentally alters the challenge that FDA faces. In 1938, when President Theodore Roosevelt established the modern FDA, we lived in a domestic economy. Our structure, our statutory paradigm, and our practices were all developed around domestic production of products. That production changed fundamentally over time, and the agency needs to adjust accordingly.
One of the major steps is the Global Pathway report, with its four pillars: forming global coalitions of regulators to strengthen the product safety net around the world; developing global data systems for sharing information across markets; using advanced risk analytics and modernizing IT capabilities; and leveraging the combined efforts of public and private third parties.
It recognizes that we can't do it all, and that we have to be smarter and more information-driven and more technology-driven. We have to learn to rely on others because it will never be possible for FDA to have enough resources to be everywhere, to see everything, to do everything.
When we talk about global coalitions and global data, I think that we would like to get to a point where we really are able to have inspectional reports from inspectorates around the globe, and we're able to share our inspection reports so that we can work with our counterparts to leverage resources.
Autor: Industry needs to ensure that it has done everything it can to assume responsibility for its supply chains, for its component suppliers, for its own production around the world. It comes down to companies really understanding what they're making and what they're buying and how they can best ensure product safety and quality.
BioPharm: What changes have been made at FDA?
Autor: At around the same time that we issued the Pathway report, the Commissioner reorganized FDA. She established four directorates—the Directorate of Foods and Veterinary Medicine, the Directorate of Medical Products and Tobacco, the Operations Directorate run by our Chief Operating Officer, and my Directorate, called Global Regulatory Operations and Policy. My mandate is to implement the Pathway report, to ensure that FDA fully integrates its domestic and international programs to best promote and protect public health, and to make import safety and globalization a top priority in the years to come.
My directorate includes OIP, which leads, manages, and coordinates FDA's global engagement work, including our 13 foreign posts. In addition, the Directorate includes ORA, which provides FDA leadership on imports, inspections, and enforcement. My job is to take all of those resources and align them against our global challenges.
I think, for example, that we ought to be treating like risks in equivalent ways regardless of where they're located. So a sterile drug facility in China should not be getting a different level of regulatory oversight than a sterile drug facility in Chicago. If you look at reports from the Government Accountability Office (GAO), you'll see that our inspection coverage on the foreign side is not nearly as frequent as our inspection coverage on the domestic side. Now, I don't think that means that in the future we inspect everybody equally all the time. But we should have equal assurance of safety and quality regardless of where the product comes from. And that can involve using our own inspections or data from our counterparts, or third-party coverage, or any other means that we can come up with.
It's an interesting challenge because, as I said, we are a domestic organization. My directorate includes 4400 people in ORA, pretty much all domestic; and less than 100 people in OIP dedicated to international work.
BioPharm: Does this mean that ORA will be shifting more inspectors overseas?
Autor: We're not necessarily spreading all our people around the globe, but we need to figure out how to use our resources to make sure that we have the best coverage of all of our global risks. It's about strategic and risk-based global industry oversight. We need to be gathering data and information, analyzing it, identifying risks, and devising targeted, tailored, strategic approaches that are flexible, that address those specific risks.
Those approaches can be anything from inspections, to enforcement, to incentives, to education and training. We need to implement those strategies, to see what works, and continue to learn and improve. Inspections are a significant part of it, but certainly not all of it.
There also is a lot of work to be done in gathering information about emerging risks, whether it's product quality defects or problematic environmental trends. It could be almost anything that helps us understand more fully the breadth of the risks and how to intervene. Right now we, and a lot of regulators, have very operational models of doing business. We go out on the ground and see what we find, and then we figure out what to do about it. That's important, but information can help us know, in advance, what the challenges are, what the risks are, and what the opportunities are.
When you think about a world with hundreds of thousands of producers in 150 countries, that's such a monumental challenge. The only way to really address it is to be as strategic and risk-based and leveraged as possible.
Autor: Yes, both industry and FDA need to be more aware of red flags for emerging risks. In the heparin situation, there was a virus killing pigs in China that caused a shortage of heparin and rising prices. We know from history that when there's strong demand, diminished supply, and high prices, that is an opportunity for criminals to step in. So we need to be smarter about looking for those kinds of things. That applies to regulators, but it also means that industry should be paying attention to what's going on in their markets; looking at procurement of components is a very important aspect of business.
BioPharm: Do manufacturers do enough to ensure product quality?
Autor: What I hear from the pharmaceutical industry is that the quality side and the supply side aren't always connected. So you have someone who is out buying components, and they're just looking for a slightly less expensive supplier. But they may not take into account the full range of costs associated with a less expensive component.
Often a component may be cheaper to buy, but it may be made at a facility far away, which is harder to really have a handle on from a quality perspective. It may be that, in fact, that component could cause a serious product quality problem, which ultimately could cost the company much, much, much more money than it ever saved by knocking a penny or two off the price of the component.
BioPharm: Do you think industry is getting this message?
Autor: I think there have been a lot of good efforts underway recently. For example, I think Rx–360 [the international pharmaceutical supply chain consortium] is a great way for industry to work together to share information, both about specific suppliers and about emerging risks and issues.
My view is that there is a range of companies. There are some that, frankly, I think are still not as proactive about quality as they could be. There are some companies that really do constantly aspire to best practices, there are others that don't, and then there are some in between. What I often hear in those situations is that there may be people in the quality units who are very vocal proponents of this, but they may not always get the attention and the resources they need from high levels of the companies.
Other industries—aerospace, automotive—have really grappled with the challenges of globalization and outsourcing and put in systems that aren't necessarily replicated in the pharmaceutical industry. There is a lot of information in the literature about how investing in quality pays dividends, and some companies have embraced that. It really starts at the very beginning in understanding your process and your product, and goes on to understanding your suppliers and your supply chain.
Ultimately, some of the risks [from producing low quality drugs] are just devastating, as with the incidence of glass particles in vials of injectable drugs. That cost industry at least $250 million. As I understand it, glass production processes can make the glass vulnerable to this damage, and a lot of very expensive injectable products had to be recalled. And the heparin crisis cost Baxter at least $30 million in sales and $4.7 billion in market capitalization. So these can be really devastating.
BioPharm: Will regulatory collaborations address some of these issues?
Autor: I would like to make sure that we are being strategic and cohesive globally in addressing criminal threats to the drug supply. Whether it's counterfeiting or cargo theft or economically motivated adulteration, I think there's a real opportunity to make sure that we take a holistic look. We need to make sure that the civil side out there monitoring facilities and the criminal side catching criminals are talking so that we're able to both punish crime—and also prevent and detect crime by building stronger regulatory safeguards and by telling industry what the risk might be and how to be proactive in protecting itself from potential risks.
Autor: It is true that the agency hasn't always had perfect results in relying on private third parties for inspections, but I think that there is real potential there. We are further ahead in our exploration with respect to devices and foods, but I think we've got what we need to get there on the drug side as well. This approach creates some real challenges, and we need to be frank about those and to figure out how to overcome them.
For regulators, it's hard to let go and to let someone else help us. But given the realities of globalization, we just can't do it alone. If we can work with others, if we can let go of control to some extent, we will have many more resources at our disposal. We shouldn't walk into this blind to the downsides, but it is possible, and I believe we can get there.
BioPharm: Another recent report from the Institute of Medicine (IOM) recommended that FDA pursue "mutual recognition" agreements of inspection findings. Is that a realistic approach?
Autor: I believe that we need to look for "mutual reliance." That means sufficient comfort with each other's standards to be willing to rely on work done by a counterpart. We don't necessarily need to go the whole way to mutual recognition agreements. I hope, over time, that regulatory standards globally will converge, something that is already happening. As we work together, we all learn from each other.
BioPharm: That IOM report also mentioned the Secure Supply Chain pilot program and greater use of low-cost technologies to oversee imports. What role can those play?
Autor: The Secure Supply Chain is a pilot project that aims to facilitate imports from companies and facilities where we have a certain level of assurance. It is in the process of moving forward and presents a risk-based concept: If you can know that certain imports are low risk, then you don't have to devote much time to them.
We also see opportunities to utilize more low-cost technologies in dealing with imports and supply chain security. One example is employing hand-held laboratory devices at the border. And in Africa there's use of a scratch-off number on a drug package that you can text in and find out if the drug is authentic. Manufacturers also are using barcode technology on brand name clothing or handbags and a call-in system to learn if the product is legitimate or not. I understand that certain large chain stores have RFID tags on underwear, so it seems that there's potential for pharmaceuticals.
BioPharm: There's another IOM report coming on counterfeit drugs; what is its focus?
Autor: We asked IOM to address the gaps globally in dealing with SSFFC drugs—substandard, spurious, falsely-labeled, falsified, and counterfeit products. How can countries and other stakeholders come together to really ensure that we are doing the best job we can in dealing with those products? Often that discussion gets mired in intellectual property issues.
BioPharm: Should we be looking for more reports on globalization from your office and more FDA foreign offices?
Autor: I think our job now is to bring the current program to life. I don't think we know, at this point, exactly what our global presence will be over time. Our foreign offices have been key to enhancing our effectiveness overseas, helping us to know our counterparts, to understand them, to gather information about emerging issues, and to be there when we need to jump in and do an inspection quickly.
We may get additional money in the 2013 budget for more inspectors in China for food and drugs. And if the Generic Drug User Fee Act is enacted, we will have a lot of responsibilities to expand foreign inspections and will need to take a hard look at how we can meet those. At the moment, we don't have any concrete plans to open new offices, but over time, we'll have to see what we need to do.
BioPharm: How will FDA be different in 5 to 10 years?
Autor: I believe that we will be more data driven, more risk-based, more strategic, more leveraged. We will be collaborating with our counterparts in global coalitions, we will be using data and advanced risk analytics, and we will be working closely with public and private third parties.
The combination of difficult economic times and quantum leaps in globalization will drive us towards being smarter and more effective and leveraged. I think that we will recognize that, given the challenges we and our counterparts all face, we can no longer afford duplicative regulatory programs; we need to find ways to work together as much as possible.