 We're very, very fortunate today to have with us at this conference Dr. Margaret Hamburg, Commissioner of the Food and Drug Administration. And I first want to thank Kate Bond and Mary Lou Valdez for their support, Karen Riley for their support and assistance in putting this together. We've had a close and very rewarding relationship with FDA and with Dr. Hamburg ever since she joined as Commissioner four and a half years ago. And we've been very impressed with the speed with which the FDA's global agenda has evolved. And of course, we don't normally think of FDA as a global health agency, but in fact it is rapidly becoming a very vital and important agency for reasons that we'll hear more about momentarily. We also were drawn to this to try and enlist Dr. Hamburg to be with us today because when we look at the MECONG, the issues are so compelling. And we'll hear more about that, both with respect to food and drug. We've heard some around the drug issues in the previous panel and in the opening panel when Dr. Hien and Dr. Orr both referenced the challenges that they face in their respective countries with fake and substandard drugs. So we're going to have a conversation here. We're going to move towards hearing from you as we have earlier in a rather brisk fashion, but we first would like to hear from Dr. Hamburg. And perhaps you could open up a bit by talking to us about what it is about globalization, that the good, the bad, and the ugly about globalization that drives you to be so active at trying to find new mechanisms, new partnerships, new consortium, new manners of capacity building, and the like in places like the MECONG. Maybe you could talk at a general level because this isn't confined to the MECONG, but this is something that's been a transformation in the thinking of FDA and the way that it thinks of itself as an organization, and it's very pronounced. And so perhaps you could talk a bit about that. Thank you. Terrific. Well, I'm delighted to be here and to see the kind of turnout for today's meeting, and I'm privileged to now be in the new CSIS building, and to talk about something that's very, very close to my heart personally as a public health professional, and to our agency, the Food and Drug Administration. This really is a critical time, and we are really restructuring and reorienting. So as was just said, we will be a global public health agency. We're a very unusual agency in the sense that we are a science-based regulatory agency with a public health mission, but play a very critical role in promoting and protecting the health of the public. And historically, our focus has been to promote and protect the health of the American people, that's what's written in law, and that is our mandate. But in fact, in the real world that we live in, in order for us to fulfill our mission, we need to recognize that it is much broader and extends far beyond our borders, and the best way for us to serve the American people is to really engage as a global community. And why are we so clear about this? It is because the health issues before us are global in nature, science that underlies the products that we regulate is intrinsically a global enterprise. The industries we regulate are increasingly global, multinational in nature. And the products that we directly regulate in terms of their use here in the United States increasingly are global in nature. There are very few products, in fact, that are exclusively made and used in the United States. If you look on the drug side, about 40% of finished drugs taken in the United States are made in another country. About 80% of the active pharmaceutical ingredients used in drugs that ultimately are consumed here are coming, manufactured in other countries. On the food side, the numbers are striking as well. Between 15 and 20% of the overall food supply is coming from other countries. About 50% of fresh produce, fresh fruits, I should say, and nuts are coming from other countries. Over 80% of seafood is coming from other countries, many in fact, much of that from the region that we're focused on today. So we really see this as essential for us to engage with regulatory authorities around the world, to look for ways that we can strengthen standards and product quality and safety around the world so that we can fulfill our mission. Plus, we really believe that as we think about what all of us in the public health sector care about in terms of global health and strengthening health systems around the world, that we need to think about regulatory capacity as a critical component of health systems. It doesn't matter what kinds of systems you have to deliver care if you cannot have confidence in the quality and the efficacy and the safety of those products, whether it's drugs or medical devices. If you cannot ensure a safe, wholesome food supply, that will undermine even the most promising health care systems. So we think that we really need to increasingly convince, sometimes it takes some convincing, even our colleagues in public health that regulatory system strengthening needs to be part of health systems development. And then when you look broader at investments in development from a health and human development perspective and an economic development, investing in regulatory systems and capacity building really makes a lot of sense. From my perspective, it's a win, win, win. Because if we are getting products coming into this country from developing economies where their regulatory systems are weak and immature, the risks in terms of the products Americans are going to be consuming are much higher because we don't have confidence that they are being produced or manufactured to the standards that we require for products used here. For those countries, if they can strengthen their regulatory standards and oversight, they can certainly ensure the health and safety of their own populations to a much greater degree. But they can also begin to really build industries that are sustainable and reliable. They can begin to really strengthen their export capacity as well as their internal domestic production. And at the end of the day, all of this enhances national and international security and the stability of countries around the world. So I think that though many in this room probably have not thought about the critical and central importance of regulatory systems in your work or in the countries you come from or in the region that we're focused on, I hope that by the end of our discussion you'll be a little bit more persuaded and you will really join us in our efforts to make critical progress in this arena. And as was mentioned, I think we actually have made some significant progress in recent years. Thank you. The Mekong, there's a couple of dimensions of this that jump out. Later in the day, we're going to have a panel on Myanmar. Now, this is a fast-breaking transition. It's very complicated. But certainly, as we were discussing earlier, this is a case where now's the moment, right? Now's the moment where many critical decisions are being made. In terms of regulatory capacity, my guess would be that there is very limited. But an enormous sensitivity around this if you talk to people about where they source their drugs. It's not through a regulated channel. And so you have one glaring challenge there. We've heard a lot about Artemis and resistant malaria and some of the data. The IOM study that you were involved in supporting earlier on fake and substandard drugs. When you read through that study, it said the scale, the magnitude of this challenge of illicit and substandard drugs is huge. The data that we have available is very, very low quality often. But interestingly within that study, it cited the actual concrete data coming out of Southeast Asia around malaria as being very graphic proof of a causal effect there. So there's a region-wide demand there. We also heard earlier today about the progress that's been made in Vietnam, in Cambodia and other. There's real capacity in these countries and a real interest in sort of looking at these. And there's more of a regionalized approach. We have the lower Mekong initiative, which we heard about, which flags this substandard and fake drug issue as one of its top priorities. So there's the time would seem to be ripe for the arguments that you're being, that you're putting forward specific to the Mekong. Maybe you could tell us a bit about how do you go about in a practical term? How do you move forward in concrete terms, the kind of partnerships you're trying to build? Some of them are country to country. Some of them are a broad consortium of regulatory agencies. Some of them may be partnerships with regional, with ASEAN or APAC or others. You seem to come at these challenges at multiple levels simultaneously with a sort of long-term outlook. Could you tell us a bit more? Yeah, well, I think it's such an important point. And we really are building whole new relationships, whole new ways of engaging with partners and trying to now begin to institutionalize some of these approaches. I think it does require many different types of partnerships and a number of different strategies and trying to be flexible and responsive to needs is a core part of our strategy. I would say that one of the things we have really come to recognize is that we do need a broad overarching system of governance that really acknowledges the fact that regulatory authorities cannot operate as isolated domains within their own countries, but really do need to work through a more internationalized platform and we're trying to create a new set of regulatory coalitions to enable this both relationship building and institutionalization of the importance of collaboration. There are many activities that are international collaborations in different domains of activity and those have proven themselves to be very important. Some of them have needed to be modernized and others really need to be built up almost from scratch, but in the area of certain standards around drugs, food, devices. So we don't want to completely get rid of the existing activities and start from scratch, but we want to build them up. We want to look for where our needless overlaps, especially at a time of physical constraint, but importantly where are the gaps and how can we fill them in, but also create an overarching umbrella for collaboration. It's very important to try to harmonize standards and approaches, but we'll never, number one, be able to have legal regulatory frameworks that are identical across all nations and regions of the world. But we need to find ways to increase trust and confidence in the work of other regulatory authorities so that we can rely on information, share information, effectively in fact in this complex world help share the workload, which is huge just as an example. We are seeing a dramatic increase in the volume of imports into the United States. I think it's quadrupled over the last decade or so with products coming from more than 300,000 facilities around the world, more than 150 countries bringing products into the United States and coming into the United States through more than 300 ports of entry planes, boats, trains, trucks, occasionally carried in by people. We have to figure out a way to monitor all of this activity. One of the ways is not to try to pretend that we can be in all those facilities or be at all those border crossings, but to have more confidence in these products and the standards with which they are produced and manufactured so that when they come in we don't have as much work to do. So finding ways not necessarily to harmonize and make everything exactly the same, but to increase capacity and mutual reliance I think is very, very critical. Working with existing international institutions and organizations such as the World Health Organization, and I think we're going to talk a little bit later about some of the work we've been doing with WHO to help increase surveillance in terms of drug quality and safety. Working with the World Bank, we have an important partnership with them and the APEC region around food safety and capacity building, as I said, trying to integrate our agenda into the development agenda, which I think is so very important. And working with the companies that we regulate as well because many of them are multinational and have a vested interest in what we're doing, and many of them that may not be multinational may see great benefit working more closely with regulatory authorities in terms of their ability to strengthen their brand and their marketplace. So there are lots of different ways that we're thinking about partnerships and of course working with health care systems and public health more broadly. But it's a lot of different activities. We feel like we've got a lot of balls in the air and we have to keep juggling. But as more partners come in, there'll be more hands to catch those balls. And I think at the end of the day, we're going to really have a very exciting new strategic framework for regulatory oversight that will make a huge difference. Thank you. What I'd like to do now is ask, and if we have microphones, ask some comments. Dr. Hien, would you like to offer a comment, Dr. Orr, if you care to? And then we have two special folks here that after you have offered your comment and questions I'd like to turn to Mick Dietz, who's from WHO's Substandard and Falsified Drugs Monitoring Project and also Suli Phanavang from US Pharmacopias Promoting the Quality of Medicine. Dr. Hien? Yes, thank you very much. In Vietnam, full safety and drug quality, including vaccine quality, very big concern of the public. Even you can see on daily newspapers, they talk about the concern about this issue. And even in our country, food safety and drug quality is in charge by different departments, Department of Safety, Department of Drug Administration. And even sometimes some problems happen with the food safety and drug quality and vaccine quality. We argue that who is responsible for this issue? Sometimes MOS, Ministry of Agriculture, Ministry of Commerce. And therefore now we start to discuss, we may apply US models for setting up FDA or even CDC system in our country. My question is, could you advise us how to start with, what is the core requirements to set up FDA in our country? Well, that's a big question, but one thing that I can guide you to is a study that the Institute of Medicine of the National Academy of Sciences here in the United States undertook at our request, which was really to try to respond to just that kind of question in terms of what is necessary to strengthen regulatory capacity in developing economies? What are some of the core elements of regulatory functioning and oversight that are really needed? And to think about the question of how can the more developed regulatory authorities help to build capacity around the world working in partnership amongst themselves and obviously with the target countries, it's not an easy undertaking and part of it is getting the attention of leadership within countries and within regions to even recognize how important this is. It's a strong economic as well as health and human development argument for why these kinds of investments make a lot of sense and really create a foundation on which many other aspects of healthcare delivery, public health and economic development and commerce can then rest. But I think that it is, it's a very complex undertaking. We're challenged at the FDA in that, you know, I'm very proud of the fact that we are viewed as the gold standard around the world and have a very established and reasonably well functioning, although not perfect enterprise, but we aren't a development agency. We have many, many roles and responsibilities here in the United States that are stretching our staff very thin and of course budget cuts looming before us as well, so our ability to do all that we'd like to do in partnership with others is limited, but that's why we have to embed this focus and this area of work into the broader development agenda into the thinking of our finance ministers and our organizations for development and commerce and why we also have to make sure that we are part of investments in strengthening healthcare and public health. Dr. Orr, would you like to offer a comment and then we'll come to Mick and to Suley. Dr. Orr from Ministry of Health Cambodia. For Cambodia, this is one of the issues that we try to tackle, you know. We have the Department of Drug and Food to deal with this issue and they are very active in working in this particular area, but it needs more engagement with our partner in order to work together because this is not only the issue in the health sector. It will require the cross-sectoral involvement, for example, the issue of drug smuggling, you know, across the border. If they smuggled something very secret, so how can we do for this, you know? Because right now we try to regulate the sale of pharmacies, you know, in the country almost 100 percent of the pharmacy register with the Department of Drug and Food. But the biggest challenge is on how we work together and I would like to hear from your perspective on how your drug and food can really help to help the country based on the experience you have in order to work together as a cross-border issue to tackle this kind of substandard and counterfeit drugs. Well it is certainly the case that the supply chains for drugs and other medical products as well as for food products are increasingly complex involving many different countries and, you know, sadly with respect to drugs, you know, increasingly corrupt where there is, you know, intentional adulteration, economically motivated and, you know, organized crime even becoming involved in the trade of substandard and counterfeit drugs so that it is a very, very serious problem on many levels and it is one where, you know, no one country can handle it alone so this broader engagement is so critical and for substandard and counterfeit drugs it requires not just working with health and regulatory authorities but law enforcement of course as well. An important component of it that I think we will be talking about in a minute is really understanding the nature and scope of the problem and it's really been tracked very poorly up until recently to even know the magnitude of the problem and how it is affecting populations in terms of access to reliable quality drugs. We certainly know with malaria as Steve mentioned that, you know, the numbers are astounding in particularly in certain regions of the world and seriously compromising our ability to manage a critical health issue and frankly to be responsible stewards of monies going towards health programs to address these public health problems. We know that through a better understanding of the nature and scope of the problem agreements and coordinated strategies in terms of greater tracking and tracing of these products from the point of manufacture through all of their circulations, distributions, repackaging and deliveries will make a difference. We know that sharing information across regulatory authorities and with companies who the legitimate companies are very troubled by compromised products that are undermining both their brands and of course the ultimate health benefits of their products and as I said, you know, also we do need to work with law enforcement because we need to really identify some of these bad actors and they need to be punished and held accountable so that we can move towards healthier systems and I think regional approaches for many parts of the world are going to be the most effective strategies because it does require complex investments and systems in order to be successful and sustained commitment like so many things. This is not a one off. We aren't going to be able to identify the problem, target an intervention and solve it. It's going to require continuous investment and strengthening a system, greater coordination over time. Mick Dietz, could we hear from you? Mick is with WHO, World Health Organization in Geneva. Mick, thank you for being with us. Now thanks for the invitation and thanks for the opportunity to speak to you. First of all, much that has been said in this session and this morning really resonates with what we're seeing reported globally in terms of substandard and falsified medicines. It is a global issue, it is interregional, one region will affect another and there is a degree of coordination that's required there. Now with FDA support, we've launched surveillance and monitoring system so that we can start to assess in a more accurate fashion the scope and scale and most importantly the harm that is caused by substandard and falsified medicines. There's a lot of misleading data out there but equally there's some really good data out there from good thorough analysis that's been carried out but usually in a close geographic area usually concentrated perhaps on one therapeutic category of medicine. So now this is a global program, we've rolled it out via a pilot through 10 countries and I'm glad to say that Vietnam and Cambodia were both pilot countries to test the system first and now we have just under 60 countries that are participating and reporting in a structured and systematic fashion so that we're looking at evidence and validated cases and we're separating out the accidental manufacturing errors against the intentionally falsified medicines as there's different strategies you can adopt to tackle each of these problems. In terms of antimalarials you know we're seeing a lot of antimalarial drugs being reported from the African region of all types, ACTs in the main, some monotherapies being reported that are falsified medicines and some of the older treatments for malaria as well but this is a difficult issue to tackle but it's really difficult to establish the harm that's caused by those medicines. If we have antimalarial with zero active ingredient how are we going to evidence the harm that's being caused? If we see an incident that occurs which is toxic contamination of a medicine which we have unfortunately seen on a number of occasions in the last 12 months they tend to get reported more quickly and you can quickly establish the harm to public health that's being caused but we need to validate evidence, we need to understand the scope and scale and extent and harm caused of the problem and then we can start to put the strategies in place to identify where the vulnerabilities were. You need to get under the skin of each of those incidents through a deeper analysis that starts to expose where the weaknesses were and where the differences in common denominators are around the world so that's the purpose of the monitoring system and we're grateful for the support that you Dr. Hamburg and your colleagues have given to this program. Thank you. Sully. This is Sully Fanavong. Would you like to say a few words? Sully's with the U.S. Pharmacopias program which is promoting quality of medicines. Thank you for the opportunity. You know the program has been funded by USAID and also the President's malaria initiative in Mekong as well as in other 31 countries around the world. We are focusing on promoting the quality of infectious diseases in these countries. One of the components is to strengthen the capacity of medicine regulatory agencies. In pre-market product evaluation, post-marketing surveillance to obtain the evidence data to support the enforcement action. And the third component is capacity building of the quality control laboratories. We know from WHO assessment in the early 90s 60% of the medicine regulatory agencies will classify as non-functional or very weak because one of the elements of these functions is the quality control laboratories which could not produce reliable data to support action. Number three is the technology or tools that help the countries to detect the counterfeit, fake or substandard medicines to support the intervention. So these are the three areas of the program that you know put in place in some countries. For example in Mekong. You know during the day that we worked in 2004, none of the lab in the region has been pre-qualified by WHO, the quality lab for example. These days we have lab in Thailand, we have lab in Vietnam with our assistance to achieve that. And we also increase the capacity of the lab in Laos to be ISO accredited, ISO 1725 for example, which produce reliable data to support enforcement. Now looking from the FDA perspective, what role FDA can play in the region? There's still a lot of gaps that need to be filled. These include for example the dossier evaluation because this region views mostly the generic product. About 95 or 90% of the product compound in this region have the API from other sources. So the concern about generic product quality. Now when we talk about generic product, we have to talk about bio-equivalent studies. Most doctors argue that there's no way that generic product can be equal quality efficacy of the general product or innovator for example. So these regulators, they have the pressure to do something about the BA-BE studies. So they need FDA to do technical assistance in this. For example, one regional workshop we just completed two weeks ago in the Philippines with the ASEAN members, 10 countries, when I'm talking about ASEAN harmonization, participate in this meeting. And we had the former FDA staff participate in there. So everyone was wow, FDA is here. Why they don't come earlier? So this is one of the things that I think FDA can play a role. Number two, when I talk about detection of counterfeit and substandard medicine from the market to support enforcement, this is one of the things FDA should be involved. I think the 3DC for example, that can be one of the device and also robust with our sample preparation for example to detect the medicine and then support the further intervention or confirm at the lab level and taking action. Number three, when we talk about ASEAN harmonization, they focus on removing or reducing the economic barrier. To harmonize on the technical issues related to food and medicines. Now, based on my observation working in Asia for 10 years now, I see that the political advancement front has been far ahead from the technical perspective. So this is FDA can play a role. How we can build the technical capacity of the region to catch up with the political advancement. They are talking 2015, one community, one identity. There will not be a poor check for example for food, for medicines. And what will happen? It will be chaotic regardless of talking about anti-medicine resistance for example. Some countries still producing monotherapy. So FDA can play a role there also. Thank you. Can I just comment on one aspect quickly. The technology issue and how FDA can be a partner and it relates to a partnership we have with USP, USAID and others. It is a challenge to really be able to leverage all of the advances in science and technology that are happening today in terms of delivering products for people. And FDA actually has a research capacity that is often overlooked. It's certainly underfunded. But one of the things we developed was a handheld device for rapid detection of counterfeit products. And we developed it actually for our own use at our border sites and our labs to enable us to do that initial screening for these products. But we quickly recognized that this handheld could make a difference in many other parts of the world that were struggling with these same issues and that it didn't take a lot of sophisticated training and it could be relatively cheap. It wasn't perfect, but it certainly was better than nothing. And so we've developed this project. It's in pilot stage now. Actually first we're in Ghana and USP's lab in Ghana is going to help us validate our findings. We intend to develop also a site in the region that we're discussing today where we know that problems of counterfeits, particularly with respect to malaria drugs, is huge. And we think that this could have a broader impact. So we're very excited about that. And I think it's yet another example of the different kinds of partnerships that can make a difference for health. We have a few minutes, a very few minutes left in our time here to have another quick round of any comments or questions. Nick, Nick White from Mahidal Oxford. And are there any others? I completely agree with you that strengthening drug regulatory activities is an important part of health sector strengthening. On the question of intelligence, I want to support Suri's plea for better bioanalytical capabilities. And I think FDA could act as a quality assurance for the quality assurance laboratories, both for blood measurements and also for pharmaceutical quality. My particular question is a lot of the genuine manufacturers are the first people to find out if their drugs are faked. Why are they not legally obliged to inform the regulatory authorities? You know, there are probably, I mean, I know there are different rules and laws in different countries. We do work closely with the manufacturers in the United States. And, you know, I think that they are very quick to report to us when there are problems. But they don't always. And I don't, you know, and I can't speak letter-in-verse to what the FDA law is on that. But there are times whether it's a counterfeiting operation that's operating external to that company or a cargo theft or something like that where some of their products, legitimate products are in fact hijacked and go missing. You know, the sooner we can learn about these problems, the more effectively we can address them. And we're certainly trying to strengthen those working relationships. But you raise an important point about what exactly is the legal framework in this country and other countries. And I'm going to take it back to our lawyers to discuss it in some more detail because I actually don't know, you know, precisely what the standards are. But building on your point in another arena that I think shows the value of mandatory reporting, drug shortages have been a huge and growing issue for a number of years in this country around a subset of products but products that really matter for health including oncology drugs and some critical care drugs. And recently, first through a presidential executive order and then through law, the reporting requirements on industry were shifted so that they were required to tell us if they had reason to be concerned that a shortage might occur, either because of manufacturing issues, business decisions they were making or supply chain issues. It used to be they only had to report to us if they were going to stop manufacturing a drug within a six month period, a drug of critical medical importance. And with that greater database, we have been able to work much more effectively to prevent drug shortages and to turn them around when they occur. So it makes a big difference the more we can share information. So thank you for your question. Sir. And we have one other, yes please. So Phil Castle Global Cancer Initiative and Global Coalition Against Cervical Cancer and I'll try not to break my neck at the same time. We have a few doctors in the room, I think. Yeah, but broken neck is not going to not. So I want to talk about in vitro diagnostics because that's the realm that I live in. And I, you know, in particular, it's important related to companion diagnostics and a whole bunch of other reasons. One of the challenges is getting, so US FDA is the gold standard in many places I go in the world. They can't even start the conversation unless the test is US FDA approved. But the problem is getting the approval, particularly because of the guidelines that the US FDA requires, it often has to be done in the United States because you have to have the same risk profile and there's a whole bunch of requirements, which makes it prohibitively expensive to get that US FDA approval even though that test would have a much greater benefit outside the United States. And so there's this catch 22 that occurs that prevents rapid approvals and often doing it in another country, you get more disease so that you can quickly accrue the end points you need. It's often cheaper to do the trial, which would then facilitate more companies coming forward to do the right studies to make their tests available. So you can see how it kind of spirals out of control. I'm all for validation. Please don't get me wrong. But how do we facilitate if the test has the same relative benefit in a population even though the disease prevalence is different and therefore the predictive values change? How do we open the door in a way that increases the rapidity with which we can get validation without compromising? Well, the issue of diagnostics is absolutely crucial for many reasons. We could spend the whole afternoon in fact talking about them. The regulatory oversight is a complex area within the United States. I think there are some urban myths about it as well. I frequently hear that we don't accept foreign studies or studies done in other countries. That simply isn't true. But we do require under certain circumstances certain kinds of validation of clinical validity for U.S. populations, bridging studies, whatever. So that's one complicated area. But we do find that sometimes people artificially narrow their options because they don't actually understand what the FDA rules are. It is a complex area. There are certain criteria for FDA validation that is currently only applying to certain diagnostics and there's something called laboratory developed tests, which historically in the United States have been subject to what we call enforcement discretion because they originally were being developed in a laboratory setting within the health institution where they were going to be used and so we did not require full FDA approval. Now many of those laboratory developed tests are being used much more broadly, are being commercially marketed and being used for very important medical interventions. So we are in the process, this is public information, of really looking at what should be the appropriate FDA role in terms of oversight of especially the high-risk laboratory developed tests and we expect there will be guidance coming out on that relatively soon. Also guidance around companion diagnostics. As I said, it's a really complicated area. The other thing I'll just mention and obviously there are lots of opportunities to connect you with the right people at the FDA for more detailed follow-up so you can better pursue your own endeavors but increasing we're seeing something that I think has great value which is that some countries are saying through their own national laws that if FDA approves a given medical device that they will accept our approval for use in their own country and that obviously enables the reach. Then there are issues about whether or not a country or region wants to take that approach and whether they need to put it into a broader context so that adjustments can be made for their own specific population needs or values or circumstances but I think that's also a model that is increasingly important in our complex resource constrained world. Thank you. We've run out of time. This has been a very rich discussion. Dr. Hamburg, thank you so much for taking the time out of your schedule to be with us today. My pleasure. Please join me in thanking the commissioners. The next phase is eating which is for 15 minutes. The food is out on the patio. We will reconvene here at 12.15 with Assistant Secretary Danny Russell and Murray Hebert so please enjoy some lunch and please come back in 15 minutes.