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A Public Health Approach to Regulatory Processes

Keynote Address at the 2013 Global Health Product Development Forum
A Public Health Approach to Regulatory Processes
Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs
Seattle, Washington
May 1, 2013

It’s a privilege to speak today before the Gates Foundation PDP Forum and to be part of this exciting meeting. I know many of you and strongly support the mission and calling of the organizations that comprise this forum. I also know that every one of you in this audience has helped change many lives for the better. Collectively, you have helped millions, and I think we have a huge opportunity before us to do even more.

In fact, the themes running through my speech today mirror many of the aspirations of the Gates Foundation and the work you all do together:

  • Innovation for the benefit of patients
  • Collaboration to use intellectual and other resources most efficiently and not redundantly, and collaboration that plays to each other’s strengths
  • Belief in the transformative power of science and technology for the good of public health
  • And to paraphrase Foundation co-trustee Warren Buffet, the courage to confront the really tough challenges.

These basic principles are crucial to bear in mind, whether you are a large company, a small start-up, a philanthropic organization, or a public health agency like the FDA.

But I know that some of you are likely to be a little uncertain—maybe even skeptical—about the role and commitments of the FDA.

Some of you might describe FDA as an agency that protects the public from unwholesome food and unsafe or ineffective medical products. Others might view FDA through a totally different lens, as a regulator that is little more than a roadblock to innovation and economic growth.

In actuality, regulation—when it’s done right—whether in the Americas, Europe, Africa, or Asia – shouldn’t be a roadblock, but rather a facilitative pathway to achieve meaningful and lasting innovation for the public good. Regulation – when it’s done right – should not only help protect and promote the health of a community, but it also should help advance stability and economic health.  

Certainly, smart regulation must be as integral a part of any successful 21st century health care system as are smart, capable health care workers and the clinics and hospitals in which they work.

Our medicines and medical devices are the tools of 21st century health care. Helping to assure that our practitioners and patients have access to quality products – products that are what they say they are and do what they say they will do, delivered through a system that assures the security and quality of the product-- is the fundamental task of any medical products regulatory authority.

Smart regulation allows us to deliver the promise of science in the service of patients, health care providers, academics—and yes, industry too.

But even those who recognize the essential role of regulators like FDA may not appreciate that the fragmentation and globalization of product development and production, and the flow of components and finished goods across borders, are forcing a paradigm shift in the way regulators fulfill their mission within their own jurisdictions.

Today, we at FDA recognize that to successfully protect the health of the American people – which is our mandate – we must think, act, and engage globally. Our interests must be broader than simply those within our own borders, and this requires us to be a part of, and act collaboratively with, a wider regulatory enterprise that encompasses medical product regulators worldwide.

As FDA Commissioner, I believe that protecting the public health—while encouraging, not discouraging, innovation whether it is a new product to treat diabetes, or to treat African trypanosomiasis – must be our goal, and it is.

How to achieve that goal, and how to work hand in glove with others to help achieve that goal in the new, often daunting global development and delivery marketplace  - especially for neglected diseases - is what I want to talk to you about today.

While we at FDA are becoming better informed about how to act globally, I am hoping that many of you in this room will be able to help us recognize how we, within our statutory mandate and mission, can be an even better partner within the global public health enterprise.

Innovation for the public good is a core element of the FDA’s mission and that of the Gates Foundation. But innovation is not just about basic research and new discoveries. As you heard Trevor discuss yesterday, it is about taking those new good ideas and translating them into products.

Products that are stable and reliable when mass produced; that have demonstrated benefits that outweigh their known risks when used for their intended purpose; and that provide real clinical benefit for people.

Innovation is also about finding new and better ways to do things to meet the needs and challenges before us. Doing things the way we have historically done them is not going to meet the needs of those we serve...not today and certainly not in the future.

This is why we are putting great emphasis on advancing what we call regulatory science. By this we mean the science of developing new tools, standards and approaches to assess the safety, efficacy, manufacturing quality and performance of medical products. Investments in regulatory science are vital.

Regulatory science helps form the bridge between important discoveries and opportunities in science, and the real world products we need; it supports and shapes the development of new and better drugs, vaccines and diagnostics, as well as more efficient processes to evaluate medical products and get them to market.

Yet it is an often overlooked, under-developed and certainly under-funded component of the overall scientific research enterprise…and this must change.

Many of you in this room today have been essential partners in our efforts to strengthen, extend and apply this work. Indeed, such collaboration is a key way that FDA is investing in and using the outputs of regulatory science to make a difference in global health.

One extraordinary effort in this realm is well known to many of you in this room:   “MenAfriVac.”  For far too long, meningococcal meningitis has been a punishing disease, especially in sub-Saharan Africa, where its tragic toll can be measured in very significant human, social, and economic losses.

However, the disease is losing its power to inflict illness and death through the work of many of you here, and others around the world. FDA scientists, working with partners in this room, were delighted to play a collaborative role in developing the technology needed to manufacture an effective vaccine and at an affordable cost.

Here’s what happened:  The Gates Foundation agreed to fund the Meningitis Vaccine Project (MVP) – a partnership between the World Health Organization and PATH.

MVP was working on a new type of vaccine, against group A meningococcus, which featured a conjugate antigen. When MVP hit a hurdle during the development stage,  FDA scientists were able to help by developing a more efficient and less costly conjugation technology;  reagents for evaluating the vaccine’s performance and safety;  and methods to monitor the manufacturing process.

FDA scientists were also able to help train MVP’s manufacturer, the Serum Institute, in the new conjugation method.

As you are aware, MenAfriVac’s Indian manufacturer was licensed in December 2009 by Indian regulatory authorities, and in June 2010, the WHO prequalified the vaccine for use in its immunization programs.
Just 18 months later, teams working in Burkina Faso, Mali, Niger, Cameroon, Chad and Nigeria vaccinated an estimated 55 million people with MenAfriVac at a cost of 40 U.S. cents per dose. That’s more than three million people vaccinated each month, across some of the most challenging terrain on earth. I understand that the 100 millionth person has now been vaccinated. 

This represents a staggering accomplishment of innovation-- massive in scope, complexity, and impact, and we are proud to have played a role.

Another ongoing case study of FDA’s scientific collaboration within the realm of regulatory science involves tuberculosis regimens. To discuss this one, I have to go back nearly a decade, to 2004, when FDA released a report entitled, “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products.” 

The report addressed a deep concern that the medical product development process was not able to keep pace with basic scientific innovation, leading to a decline in new product marketing authorization submissions to the FDA. The report laid out a vision to modernize the so-called “critical path” that leads from scientific discovery to the patient.

“Critical path” is an important term in the field of medical product development. It’s also in many ways a synonym for strength-based collaboration. The critical path begins when products are selected for development and successively undergo more rigorous evaluation steps as they move to preclinical development, the clinical proof of concept and confirmatory development phases, the application for marketing approval, and the post-authorization oversight and further learning stages when the product is in wider-spread use.

Whether developing a product for a neglected disease or any other disease, we must have  development pathways that are sound, science-based, efficient, predictable, and that result in quality products that are safe, effective and available to patients.

That’s why FDA and many of our colleagues in other regulatory agencies around the world play a very active role collaborating with scientists in academia, NGOs, and companies to identify challenges to product development and increase the likelihood of success.

Returning to my TB example, when I was New York City Health Commissioner in the early 1990s, I grappled with an epidemic of resurgent TB in the city, and one that was complicated by the serious challenge of drug-resistance. Thanks to political commitment from the Mayor and others, adequate resources and a well-designed, cross-cutting program that we were able to implement, we witnessed a decline in TB cases by 46% between 1992 and 1997. For the most drug-resistant cases, the drop was 86%.  

However, as we all recognize, the global TB crisis today is far from resolved, and global action is needed to advance the tools and treatments required. The Gates Foundation TB strategy for 2011–2016 addresses many of the factors associated with the TB epidemic. Priorities include the development of new vaccines and therapies as well as innovative and accelerated approaches to vaccine and therapeutic product development, and a focus on creating shorter, simpler treatment regimens.  

As part of the global imperative to combat TB, in 2010, the FDA signaled a bold new approach. We issued a draft “Guidance for Industry:  Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination.” 

The draft guidance enables the study, in a more timely and less costly manner, of several new drugs in combination rather than studying each one separately. It reflects the realities of treatment needs for this disease, but also presents some real scientific challenges. But it is a great opportunity for collaborative research among the best minds in science, whether academia, industry, or government, including regulators – and we need to work together to get it right.

Also in 2010, the Critical Path to TB Regimens Initiative (CPTR) was launched by the Gates Foundation, the TB Alliance and the Critical Path Institute to accelerate the development of new TB drugs.

This initiative is a collaboration of industry, civil society, government, and global regulatory officials, working together to support advances in regulatory science, the development of infrastructure, and progress in the development and availability of new TB treatments.

A starting point for CPTR was identifying TB data standards that would help the research and regulatory communities conduct, submit and review their work.

The new tool – which is a standardized way to report research data – allows researchers for the first time to combine and evaluate data from multiple studies using a common approach.

The potential value of this kind of thoughtful focus on development was underscored last December when FDA approved the first new TB drug in 40 years. And we approved it in only six months after the marketing application was submitted, through an expedited pathway that was facilitated by significant interactions between the developers of this product and the regulators.

Though this new TB drug did not come directly through the CPTR initiative, its development reflected many of its elements and offers real hope of more to come.

This leads me to an earlier point. We know that early and close collaboration with regulators can reduce development and review times in very meaningful ways.  We can say that with confidence, because of our recent look at the development times for new drugs.  

We examined new drugs that were approved with the benefit of what we call pre-IND meetings (which occur right before the earliest phases of human testing), and compared them to the development times for drugs that were approved without such meetings.

While there may be multiple factors at play, the findings underscore the value of early communication. For all new drugs approved by FDA between 2010 and 2012, the clinical development time was some 3 to 5 years faster when such meetings were held.

Similar results have also been reported by the European Medicines Agency, looking at those who engage with their scientific advice program as opposed to those who don’t.
This is an important message: engagement with the appropriate regulatory authorities early in development offers products the best chance of success.

Regulators should not be thought of as a dreaded barrier to get over, engaging only at the end of the process (for example, when you submit your marketing application).

Rather the relevant regulators should be partners from the earliest stages of product development, so that you have the best chance of having a product that offers the type of benefit needed, and can be scaled-up and well-manufactured in a deliverable, usable form.

To spend millions of dollars developing a product and not be able to manufacture it correctly or not be able to extract crucial answers from the clinical trial design, is indeed a terrible waste of money, time, talent, and potential. 

Not only does every product need a well thought-through scientific research and development plan, it needs an equally well thought-through and coordinated regulatory strategy plan.

I want to finish my remarks to you today by exploring the need for stronger regulatory systems around the world as a positive force for the public and economic health of communities globally.

As I said at the outset, FDA is of necessity becoming a more globally-focused public health agency. Drugs manufactured in countries around the world account for 40 percent of the medicines we use in the United States. And 80 percent of the manufacturers of active pharmaceutical ingredients in U.S. drugs are located overseas. 

Therefore, it is absolutely essential that we have regulations and procedures in place--not just here at home but abroad as well-- to ensure that medicines we rely on are quality products, no matter where they come from. After all, lives and well-being are at stake if drugs are of questionable quality.

Our vision is to help create and be a part of a stronger global product safety net.

One of the greatest threats to patient safety involves substandard and falsified medical products in the supply chain.

Substandard and falsified drugs have numerous public health consequences, including poisoning because of toxic ingredients, too much or too little of the active ingredient, inadequate treatment or untreated disease and the development of drug-resistant disease strains. It can be the wrong medicine, or no medicine at all.

A high prevalence of substandard and falsified medicines also erodes public trust in the health care system. For the past several years, FDA, along with counterpart regulators around the world, has been engaged in global efforts to improve collaboration in preventing, detecting, and responding to this threat. It is an international problem that requires international cooperation.

For those of you who have devoted your professional life to discovering new medicines for neglected diseases and for the patients who are depending on your efforts, it is a travesty that we have a product distribution system that does not assure that they actually get those medicines at the right dose and formulation.

This sad reality needs to be confronted, and represents a concern as compelling as the need to develop the products in the first place.  To address one issue without addressing the other will not solve the global health problems you are working so hard to solve.

To further extend our global understanding and impact in this important arena, in 2011 FDA commissioned the Institute of Medicine (IOM) to examine how falsified and poor quality drugs affect the health of people around the world. Briefly, here are some of the findings of the IOM report:

  • Neglecting good manufacturing practices is the root cause of poor quality drugs. However, quality practices require resources. Many of the countries in which people sorely need medical help just don’t have the financial wherewithal and other resources to mandate and monitor these good practices.
  • Bad medicines, whether sold in street markets or on unregulated websites, are a grave public health problem. They often fail to help—and often harm—the very people who most need them. In addition, they may promote antimicrobial resistance which harms us all.
  • Crime and corruption drive the business of substandard and falsified medicines, and they are rampant in many parts of the world when a month’s supply of certain medicines may cost as much as a person’s wages. The poorest patients have little choice but to buy their medicines from vendors who sell products of questionable quality.
  • In modern supply chains, medicines can change hands many times, in many countries, before they reach patients. Each exchange provides the opportunity for unscrupulous behavior on the part of manufacturers and distributors.

In 2010, the FDA and the WHO entered into a cooperative agreement to build a global surveillance and monitoring system for substandard and falsified products and supply chain threats. The system was designed with WHO, along with the input from FDA supply chain experts as well as experts from other stringent regulatory authorities. Since September 2012, it has been piloted in 10 countries, and is generating reports, investigation and trend analysis.

This system, to be scaled up in the coming year, will enhance our global understanding of immediate threats and support risk analysis and better-informed collaborative regulatory action.

As many in this room know better than I, the problem of substandard and falsified medicines is particularly acute in the case of malaria. Recent reviews indicate that between a third and two-thirds of anti-malarial medicines in Sub-Saharan Africa and Southeast Asia are substandard or falsified.

Last week I was excited to announce a public-private partnership to explore whether an FDA-developed portable tool, known simply as Counterfeit Detection Device-3, or CD-3, can be useful  in identifying  falsified or substandard anti-malarial drugs in challenging portions of low and middle-income countries.

This device was developed by FDA scientists, and we use it now in our screening of products at points of entry into the U.S. It has the potential to be a much broader, front-line tool in other countries around the world. Joining FDA in this endeavor are the Skoll Global Threats Fund, the U.S. Pharmacopeia, the National Institutes of Health, the Centers for Disease Control and Prevention, and the multi-agency President’s Malaria Initiative, led by the U.S. Agency for International Development. The CD-3 will be field tested in Ghana. Based on our findings there, we will expand the program to other high malaria burden regions, and we have an agreement with Corning to scale-up production and availability of the CD-3 tool.

We are excited that a technology that we developed in our own lab for our own use may, in fact, have global impact by offering a new regulatory tool to support public health.

Our global health partners in the U.S. Government have begun to recognize the need to support greater regulatory capacity in other nations for sustainable delivery of safe, effective, quality products. To help us better understand how regulatory systems can be strengthened in low and middle income countries we asked the Institute of Medicine to identify major needs and gaps, and then recommend a strategy. The IOM produced an invaluable report entitled “Ensuring Safe Food and Medical Products through Stronger Regulatory Systems Abroad.”

It is a report worth reading, and underscores the enormous benefits-- and  urgent need—for the FDA, other federal agencies, other national regulatory authorities, development agencies and international organizations – to provide technical expertise, training and tools to regulatory systems in low and middle income countries. We are committed to this proposition.

As I said earlier, we believe strongly that a well-functioning regulatory system is as integral a part of any 21st century health care system as are the practitioners and the facilities in which they work and use the tools the regulatory system validates and secures.

As governments, multinational organizations, NGOs, and others view the larger health care system development efforts globally, not to include medical products regulatory capacity building within those efforts is done at the peril of those whom they are trying to serve.

Efforts are already underway to support and collaborate with regulatory systems across the globe, such as our foreign training programs on good clinical practice inspections and generic drug review requirements and processes; a medical products information “hub” for the Americas in collaboration with the Pan American Health Organization; our interagency agreements with the U.S. 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 activities my agency has been involved in. Much more is happening as well – by the U.S. and others – as this issue gains greater and greater traction and priority in the health care system development family, including development banks, regional economic communities and public health institutions.

And with respect to our commitment to these endeavors, I want to mention an exciting development. Beginning today, FDA is assigning Dr. Mac Lumpkin to serve on detail as a senior fellow of the Gates Foundation. Mac is one of our most senior, expert, respected and accomplished physician scientists and leaders at the FDA. In his 23 years here, he has served in many key roles, importantly as Deputy Director of the Center for Drug Evaluation and Research and most recently, as Deputy Commissioner for International Programs. He has been an enormous catalyst for the repositioning of the FDA to respond to the challenges of globalization, and I think that we are all extremely enthusiastic about this new opportunity for greater partnership with the Gates Foundation. He will be working on all of the kinds of issues I have been discussing, and let me mention one more.

I know that the Gates Foundation is now focused also on trying to help rationalize the various regulatory processes required to get effective, quality products for neglected diseases to those who need them. Looking at ways the global regulatory enterprise might truly leverage the work and resources of regulatory agencies, various strength-based partnership options are being discussed. 

Mexico has already taken steps in this direction. It now relies on the Good Manufacturing Practices certificates of six foreign agencies (FDA, ANVISA (Brazil), Health Canada, Pharmaceutical and Food Safety Bureau (Japan), TGA (Australia), and EMA (European Union)) to make their regulatory decisions.

In addition, in furthering the idea of reliance on others, it uses the reviews and work of authorities in the U.S., Canada, and Japan – if those agencies have already authorized the product – to make their own regulatory decision for their country.

The results of these policies have been dramatic. There have been large savings in administrative costs, and a decrease in the regulatory burden.

Specifically, because of third party pre-verification, application waiting times have been reduced from one year to less than a month, and they have released 157 new generic medications and 31 innovator drugs. With the savings derived from the strategy to liberate generics, COFEPRIS, the Mexican regulatory authority, estimates that an additional 750,000 patients can be treated in four years.

This is just one example of how regulatory systems and processes can be rationalized in the global context.

The Gates Foundation’s early investments in efforts like the African Medicines Regional Harmonization are at the forefront of this frontier field of global health. The Foundation remains actively and strongly engaged with the World Bank, the WHO, the African Union and the leadership of the East African Community in this effort.

And the FDA has advocated strongly for U.S. government support, especially in the areas of safety surveillance and encouraging other African economic communities to develop and submit their own regulatory rationalization/harmonization plans – such as was done by the EAC.

As I’ve tried to highlight, regulatory systems play an essential role of promoting public health, economic health, and innovation both here in the United States and in other parts of the world.

But building a strong global safety net requires broad strength-based collaboration of many partners. It was crucial to the success in fighting meningitis in Africa, in our work with TB regimens, and in identifying and working to eradicate substandard and falsified medications 

As I was preparing for this occasion, I was struck by a paragraph from a Gates Foundation publication which elegantly encapsulates the foundation’s public health mission.  It reads:

“We Cannot Do It Alone. Our grantees and partners are at the center of our work. To create solutions with impact, we seek mutual understanding and collaborative partnerships. We engage with our grantees and partners in a spirit of trust, candid communication, and transparency.”

At the FDA, our goal is not only to strengthen regulatory science to advance innovations so that life-saving treatments, diagnostics and vaccines can be developed and reach patients, but also to keep harmful products out of the market and help secure the integrity of our global supply chain.

But like the Gates Foundation, we cannot do it alone. And it is our great fortune, in this endeavor, to have the Gates Foundation – and all of you in this audience -- as our valued and worthy partners.

Thank you.