In a country full of differences, common ground

By: Michael Taylor, Howard Sklamberg and Camille Brewer

We are headed to a meeting in Delhi. Through our taxi windows a vibrant India swirls around us: green and yellow motorized rickshaws and Vespas dart through the crowded city streets, zipping around buses, trucks and the occasional courageous pedestrian. It looks and feels like no city in the United States.

Michael Taylor

Michael R. Taylor, FDA’s Deputy Commissioner for Foods and Veterinary Medicine

We are struck by how different it all seems, with many manifestations of traditional Indian lifestyle and culture — saris and turbans worn by many women and men, cattle and monkeys in the streets, and street food of all kinds — mixing with advanced urban infrastructure, intense commercial activity, and Western brand names all around.

We’ve come to this amazing country to discuss with government officials and industry leaders some important changes to our food safety system that will  affect food exports from here to the United States. But we are also here to sign a Memorandum of Understanding (MOU) with the government of India, “intended to develop opportunities for cooperative engagement in regulatory, scientific, and technical matters and public health protection that are related to…food products.” It admittedly sounds like a bit of legalese, but what it means is that it’s critical that our two nations work together on food safety issues.

Howard Sklamberg

Howard Sklamberg, FDA’s Deputy Commissioner for Global Regulatory Operations and Policy

Why? Well, India is the 7th largest supplier of food to the United States. The great amount of Indian food products that wind up on the dinner tables of Americans every night — including shrimp, spices, and rice — reflects the increasing globalization of our own country’s food supply, 15 percent of which consists of foreign products. Many of these goods come from any one of India’s 29 states, produced by thousands of different companies.

The signing of this MOU with the Export Inspection Council of India is the next step in enhancing our regulatory cooperation with this nation of 1.2 billion people. Last year, while here, FDA Commissioner Margaret A. Hamburg, M.D., signed a similar arrangement between FDA and the Indian Department of Health and Family Welfare, a Statement of Intent focused on medical and cosmetic product safety.

And while these documents serve as important, even historic, markers of our nations’ shared commitment to quality drug and food products, we’ve also discovered we have a lot in common with those we’ve met on our journey — which is taking us from the stalls of nut and spice vendors in Old Delhi to a shrimp processing facility in a remote part of Andhra Pradesh.

Camille Brewer

Camille Brewer, M.S., R.D., Director of International Affairs at FDA’s Office of Foods and Veterinary Medicine.

We had a lot of information to share on this trip. The Food Safety Modernization Act (FSMA), signed into law by President Obama in 2011, mandates a food safety system that is preventive rather than reactive, and in which foreign food producers are held to the same safety standards as our domestic farmers and food companies. Under FSMA’s new import safety system, we will continue targeted border checks, but the new system makes importers in the U.S. accountable to FDA for verifying that their foreign suppliers are using methods to prevent food safety problems that provide the same level of public health protection as those used by their U.S. counterparts.

Under FSMA, this new accountability for importers will be backed up by more overseas inspections by FDA, and, crucial for the purposes of this trip, more active partnership with our foreign government counterparts. We need it to strengthen assurances of food safety and capitalize efficiently on the efforts of all participants in what is becoming a truly global food safety system. FSMA is a game changer for food safety and for our food safety partners around the world, and we wondered how our talk about its implementation would be received.

But the Indians are no strangers to sweeping change to improve food safety.

India Shrimp Plant

FDA’s Howard Sklamberg (left) and Michael Taylor (center) tour Waterbase Ltd, a shrimp processing plant and farm in Nellore, India.

Our counterparts, known as the Food Safety and Standards Authority of India (FSSAI), are also undergoing a significant regulatory overhaul, known as the Foods Safety and Standards Act. Passed in 2006, it was the law that actually created FSSAI. At its core, the Act seeks to ensure that India’s food industry is adhering to international, science-based standards for food safety. Not unlike FSMA, this law poses many challenges in terms of how it can be successfully implemented, with both laws mandating comprehensive change, including marked increases in authority that require new resources to implement.

India MOU signing

FDA’s Howard Sklamberg (left) and Michael Taylor (center) sign a Memorandum of Understanding with the government of India

Although we don’t know most of the 22 official languages spoken here, we nonetheless realized after meeting with FSSAI that we “speak the same language” in terms of our food safety challenges and solutions. The FSSAI leaders conveyed real concern about protecting the Indian consumers they serve and, like us, they understand that in an increasingly global world, you can’t “go it alone” when it comes to food safety. Commissioner Hamburg, speaking of the global drug supply and how to make it safer, once described the need for a “coalition of regulators.” That same need exists for the world’s food supply.

We left our meeting with FSSAI assured that we are on the same page with our Indian colleagues about our food safety goals, as well as the amount of work — and collaboration — needed to achieve them.

The sounds and sights of Delhi and D.C. are certainly different. But with our MOU signed, we look forward to building our partnership with India, recognizing that sometimes the most fruitful relationships result when people with diverse perspectives come together to find common ground.

Michael R. Taylor is FDA’s Deputy Commissioner for Foods and Veterinary Medicine

Howard Sklamberg is FDA’s Deputy Commissioner for Global Regulatory Operations and Policy

Camille Brewer, M.S., R.D., is Director of International Affairs at FDA’s Office of Foods and Veterinary Medicine.

From New Jersey to New Delhi, a global focus on quality

By: Howard Sklamberg and Cynthia Schnedar

As we walked through the bustling, ancient city streets of Old Delhi last week, teeming with tourists and shop keepers selling spices and saris, we were struck by how resplendent this country is, and just how much it offers the world.

Howard Sklamberg

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

This is certainly true about prescription drugs. India is a significant exporter of generic drugs to the United States. The American people benefit tremendously from generic drugs, as more and more generic medications reduce costs for patients, and the American healthcare system. The rise of India’s pharmaceutical star is one of the reasons why our trip to India is so important.

While here, we have had a chance to meet with our regulatory counterparts in the Indian government, as well as the drug manufacturers that are either based here, or who have facilities in the country. Needless to say, we are learning a great deal.

It’s no secret there have been challenges associated with the quality of generic drugs coming out of some facilities in India. Some people have asked us here if the FDA is “singling out” India for increased inspections. We simply reply that increased exports to the U.S. result in increased inspection, no matter where you are in the world. FDA inspections ensure that when a firm wants to export drugs to the United States, the drugs meet FDA standards and will be of the quality patients and consumers want and deserve.

Cynthia Schnedar

Cynthia Schnedar, J.D., Director of the Office of Compliance at FDA’s Center for Drug Evaluation and Research

And we’ve been happy to hear that this focus on quality is, in fact, a shared goal, held by both the Indian — and India-based — regulators and pharmaceutical manufacturers with whom we’ve met. They understand what we mean when we tell them the FDA is interested in helping to build a global network of quality; that it doesn’t matter whether a drug is made in Hoboken or Hyderabad, if it is intended for use in the United States, the drug, and the way and under what conditions it’s produced, will be reviewed using the same standards and levels of scrutiny.

That scrutiny, by the way, doesn’t always have to have negative results. The inspections associated with drug production have been a central discussion point on this trip, and we’ve brought news that has been well-received, especially by the drug industry. We shared our proposed plan to create a new approach to facility inspections, one that will not only note problems, but will also allow our inspectors to document where a firm’s quality management system exceeds what would be required to meet regulatory compliance. To put it simply: the inspections can yield also carrots, and not just sticks.

Meeting in India

Last week, FDA’s Howard Sklamberg and Cynthia Schnedar participated in a panel discussion on drug quality with drug associations in India

So what are the carrots? These findings could be used to influence the frequency of our inspection of a particular facility, and possibly even support regulatory flexibility around post-approval manufacturing changes. These kinds of decisions would be anchored by data that proves that the risks of manufacturing problems in a certain facility are minimal.

We have often said we cannot inspect our way to absolute drug quality. Many of our discussions on this trip have focused on the importance of firms enhancing their own “quality cultures.” And, to that end, we know there are initiatives we can take to help them succeed. For example, we will be piloting a new questionnaire that could be used to further standardize inspections, with the goal of uniformly harvesting the kind of data that supports accurate measures of quality. We believe that by improving the inspection process in this way, future “metrics” that define quality will be understood and aspired to by manufacturers — no matter where they are in the world.

CEO meeting in India

Last week, FDA’s Howard Sklamberg and Cynthia Schnedar met with pharmaceutical CEOs in India to discuss drug quality

Of course, enforcement has been, and will continue to be, an important part of our program to ensure drug quality. Enforcement is a particularly appropriate tool when a firm does not submit accurate data to us. FDA relies on information to do its job, and faulty information means that we cannot ensure the quality of the drugs that the firm produces.

It is already clear to us, after speaking with regulators and industry leaders here, that India intends to be part of that global community that is committed to producing the highest quality of drugs possible. Through workshops and joint inspections, we continue to work with the Indian government to raise awareness and understanding of our inspections processes. And to the industry leaders we have met with here, we have pledged to continue to collect their feedback on how we might be able to help them improve regarding quality issues, and to incentivize them to do so.

India has a significant spot in the constellation of drug-producing nations. As one Indian official so eloquently said to us, we have “a galaxy” in common. And, we are happy to add, that the brightest star in that galaxy may just be our shared commitment to a global system of drug quality.

Howard Sklamberg is FDA’s Deputy Commissioner for Global Regulatory Operations and Policy

Cynthia Schnedar, J.D., is Director of the Office of Compliance at FDA’s Center for Drug Evaluation and Research

FDA Continues to Lead in Precision Medicine

By: Janet Woodcock, M.D.

Everyone knows that different people don’t respond the same way to medications, and that “one size does not fit all.” FDA has been pushing for targeted drug therapies, sometimes called “personalized medicines” or “precision medicines,” for a long time.

Janet WoodcockTargeted therapies make use of blood tests, images of the body, or other technologies to measure individual factors called “biomarkers.” These biomarkers can then be used to determine who is most likely to benefit from a treatment, who is at higher risk of a side effect, or who needs a different dose. Targeting therapy can improve drug safety, and make sure that only people likely to have a good response get put on a drug.

Targeted therapies have gained public attention since President Obama announced a Precision Medicine Initiative in his most recent State of the Union address. This initiative will reinforce our work at FDA, where development of targeted drug therapies has been a priority since the 1990s. In 1998, FDA approved the targeted therapy, Herceptin (trastuzumab), offering new hope for many patients with breast cancer. High levels of a biomarker, known as “HER-2,” identified breast tumors that were more likely to be susceptible to this drug.

Since the approval of Herceptin, the development of targeted therapies has grown rapidly. FDA’s Center for Drug Evaluation and Research (CDER) approved 30 targeted therapies since 2012, including Kalydeco (ivacaftor), a targeted drug for cystic fibrosis. In 2014 alone, eight of the 41 novel drugs approved were targeted, including:

  1. Lynparza (olaparib) for the treatment of advanced ovarian cancer.
  2. Blincyto (blinatumomab) for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL).
  3. Harvoni (ledipasvir and sofosbuvir) to treat patients with chronic hepatitis C infection.
  4. Viekira Pak (ombitasvir, paritaprevir, dasabuvir and ritonavir) for the treatment of chronic hepatitis C infection.
  5. Cardelga (eliglustat) for the long-term treatment of Gaucher disease type 1.
  6. Beleodaq (belinostat) for the treatment of peripheral T-cell lymphoma.
  7. Zykadia (ceritinib) to treat patients with non-small cell lung cancer (NSCLC).
  8. Vimizim (elosulfase alpha) for the treatment of Mucopolysaccharidosis Type IV (Morquio Syndrome).

Since the 1990s, FDA has also been working on personalized drug dosing. People differ in how they eliminate a drug—some eliminate it much more slowly than most other people and are susceptible to overdosing, and others eliminate it much faster, and may not get any effect. There are biomarkers to identify people who have these unusual results, and CDER has been actively working for more than 15 years to put these findings into drug labels, so that each patient gets the correct dose, particularly for highly toxic or critically important drugs.

Personalized drug safety has also gotten attention. Often, one person experiences a serious side effect that does not affect thousands of others. Science is beginning to unlock the reasons for these rare toxicities, and the labels of some medicines advise screening people to make sure they are not at high risk for a severe side effect. This can make drugs much safer.

CDER has been recognized with awards from the Personalized Medicine Coalition and the Personalized Medicine World Conference for its longstanding work in this area.

CDER uses a lot of flexibility when reviewing applications for targeted drugs. Targeting people with a good chance of response means fewer people are eligible for a drug. CDER has adapted to the resulting small development programs. For example, among the targeted therapies approved in recent years, almost 60 percent were approved on the basis of one main clinical trial along with supporting evidence. In addition, 90 percent used one or more of FDA’s expedited programs such as Breakthrough, Fast Track, Priority Review and Accelerated Approval.

It is still hard to develop targeted therapies for many diseases, because there isn’t enough scientific understanding of why the disease occurs and what biomarkers would be useful. For many common illnesses, much more research is needed to reveal the individual differences that would enable development of targeted therapies.

We still have much work to do. However, we are pleased to see substantial progress and look forward to continuing our efforts to advance biomarkers, which will help bring additional important new therapies to patients in need.

Janet Woodcock, M.D., is Director of FDA’s Center for Drug Evaluation and Research

Turning the Tide on Ebola

By: Calvin W. Edwards, CAPT, U.S. Public Health Service Commissioned Corps

Before accepting their agreements to work in Liberia in a mobile hospital for Ebola patients, I emailed each of the 68 Commissioned Corps officers of the U.S. Public Health Service that they would face danger, needed to accept certain risks, and that they would have to perform under extremely austere conditions.

Capt. Edwards

Calvin W. Edwards, CAPT, U.S. Public Health Service Commissioned Corps

Turns out, if anything, I may have underestimated the hardship.

Initially we lived 12 to a room in two-bedroom cabanas that were intended for four people and had ”septic” issues (sewage backups and overflowing toilets) to boot. We ate MRE’s (Meals Ready to Eat) intended for troops in combat. Six weeks into the two-month deployment, we were moved into tents next to the mobile hospital, about 20 officers per tent.

We worked 12-hour shifts in 90 degree heat and 90 percent humidity, often wearing head-to-toe heavy layers of plastic gear that left us soaked in sweat within minutes. A single slip in protocol could expose us to a deadly virus as we worked with vomiting patients who could defecate up to three gallons of diarrhea a day and could quickly dehydrate.

The Payoff

But when the first patient emerged with a clean bill of health, the hardships were forgotten.

A Liberian physician’s assistant, a man in his 30s, was the first to walk out with a certificate documenting that two tests showed him to be virus-free.

Ebola Survivor

U.S. Public Health Service officers celebrate as a Liberian man adds his handprint to a “survivors wall.” Each patient who overcame Ebola after treatment at the USPHS mobile hospital outside Monrovia was given a set of clothes and essentials and invited to mark their recovery with a handprint.

His family arrived like a chorus, singing, praising God, thanking America, jubilantly crying, and shouting, “He lived!”

This ex-patient became the first person to dip his hand in yellow paint and make an imprint on our “survivors’ wall.” Although total numbers have not yet been released, there were more handprints to come, and more patients survived than died.

Each patient who walked out confirmed that we were correct deciding to cross an ocean to help stop the spread of Ebola. To see a once desperately sick person recover and go home, knowing we had a part in that, was more satisfying than I can describe.

We were the first group of Public Health Service officers to move to the tents that were set up as a hospital in Liberia. Our group, which I commanded, included 24 women and 45 men. I had three weeks’ notice before flying out; some in our group had as little as five days to decide and be deployed.

Since our return, two more groups of Public Health Service officers have been deployed to the hospital built in a remote area about 1.5 hours from downtown Monrovia. The final group is still there.

The Mission

Our mission was to treat health care workers who contracted the Ebola virus. Before our arrival health care workers were leaving in droves, and the volunteer pool was drying up. The creation of our treatment facility helped turn the tide.

Liberia Compound

An aerial photo shows the mobile medical compound where Public Health Service Officers treat health care workers who contract Ebola.

The Liberian Ministry of Health told us that some health care workers were waiting until we had set up the facility before agreeing to come to Liberia. The fact we had a small part in increasing the pool of workers treating desperate patients was awesome. How often in our lives do we get a chance to do something so big?

On the other hand, one of our greatest stresses was how little we could do to help defeat the virus. Often the most we could do was keep people clean and hydrated while hoping their bodies would develop antibodies.

It was especially hard emotionally when we lost a patient at night. Because Ebola patients are most infective right after they succumb to the disease, we could not risk moving them over the dimly-lighted pathway to the morgue.

The Public Health Service officers were the only people working in the hospital. They performed every job, even those most unpleasant, and did it regardless of rank, exalted skills, or letters after their names. Yet all came away happy about the role they played.

For my part, I am both humbled and intensely proud of these men and women — of their skills, dedication, selflessness, ruggedness and resiliency. I wish all Americans could share some measure of my joy.

CAPT Edwards is a Public Health Service officer who serves in FDA’s Office of Regulatory Affairs. The U.S. Public Health Service Commissioned Corps is made up of 6,500 public health professionals who provide leadership and clinical service roles within the federal government agencies to which they are assigned.

In India, With Our Sleeves Rolled Up

By: Howard Sklamberg and Michael Taylor

Howard Sklamberg

Howard Sklamberg

These facts surprise many people, but roughly 80 percent of active pharmaceutical ingredients, 40 percent of finished drugs, 80 percent of seafood, 50 percent of fresh fruit and 20 percent of fresh vegetables come from outside of the U.S.

Each year, the FDA has to assess millions of products grown, harvested, processed, manufactured and shipped from outside of the U.S. And one of the most impressive examples of how this globalization of production, consumption and trade has altered the regulatory landscape is India.

India is quickly becoming a significant player in the global marketplace, representing an important source of FDA‐regulated products. With a diverse population, highly skilled work force, and favorable economic conditions, India has become an increasingly attractive location for companies to operate.

Michael Taylor

Michael Taylor

And with that, Indian regulators have become important strategic partners for FDA. Today, we regularly engage with them on everything from sharing information on clinical trials to collaboratively addressing product safety issues that may harm American consumers.

When Commissioner Hamburg visited the country last year, she remarked that the “rapid globalization of commerce has posed significant challenges to ensuring consumer safety as the number of suppliers entering the U.S. has increased.” On her visit she signed a milestone Statement of Intent between our two countries  seeking to “collectively work together to improve the lines of communication between our agencies and work diligently to ensure that the products being exported from India are safe and of high quality.”

We are eager to continue the work she started. And improving the lines of communication of which she spoke is the purpose  of our working visit to India. Before the trip we discussed with our teams what we expect from our journey. Our top goal is to listen and learn. We want to understand what challenges the Indian government is facing with regard to drug and food safety. We want to hear from both American companies operating in India, as well as Indian manufacturers. And we want to discuss with our Indian counterparts a number of significant changes in the American regulatory system that affect our relationship.

FDA’s Howard Sklamberg, Deputy Commissioner for Global Regulatory Operations & Policy, and Cynthia Schnedar, Director, Office of Compliance at CDER, meet with Dr. G.N. Singh, Drugs Controller General of India.

FDA’s Howard Sklamberg, Deputy Commissioner for Global Regulatory Operations & Policy, and Cynthia Schnedar, Director, Office of Compliance at CDER, meet with Dr. G.N. Singh, Drugs Controller General of India. Get this and other photos from FDA’s trip to India on Flickr.

It is no secret that relationship has been challenged in the recent past by lapses of quality at a handful of pharmaceutical firms. And while our first regulatory responsibility is to protect the American patient and consumer, we are also very willing to collaborate with Indian regulators and other stakeholders to ensure the achievement of highest standards of safety and quality, something we feel only benefits both nations.

We have harvested some of the fruits of this cooperation already. A significant example of collaboration between the U.S. and India occurred in 2012, when a Salmonella outbreak was traced to a manufacturer in India. An FDA inspection confirmed that the tuna product implicated in the outbreak came from the suspect facility, and the Indian government revoked the manufacturer’s license.

In yet another case, FDA’s India office worked with other United States government agencies to inform industry and Indian regulators about issues associated with an import alert for Basmati rice from India. The FDA office shared laboratory procedures for testing of pesticides.

More recently, in November of 2014, as a continuation of FDA’s efforts to strengthen the quality, safety and integrity of imported drugs, the FDA India Office, in collaboration with our Center for Drug Evaluation and Research’s Office of Compliance and the Office of Regulatory Affairs, held four workshops in India.  The workshops were held in partnership with European Directorate for the Quality of Medicines and Drug Information Association and involved the Indian Drug Manufacturers Association, Parenteral Drug Association and Organization of Pharmaceutical Producers of India. Over 560 participants from the pharmaceutical industry attended the four two-day workshops.

We are confident our trip will yield more examples of such fruitful collaboration, moving the regulatory relationship between two of the world’s largest democracies to the next stage, from the intention to work together, to the ability to work together to solve the complex globalization issues facing both nations.

Howard Sklamberg is FDA’s Deputy Commissioner for Global Regulatory Operations and Policy

Michael R. Taylor is FDA’s Deputy Commissioner for Foods and Veterinary Medicine

FDA Advances Medical Product Innovation

By: Margaret A. Hamburg, M.D.

On March 10, I had the pleasure of appearing with my colleague Dr. Francis Collins before the Senate Committee on Health, Education, Labor and Pensions to testify at a hearing on the subject of “Continuing America’s Leadership in Medical Innovation for Patients.” I thought the broader public health community would be interested in my oral testimony, and so I am sharing it here:

Margaret Hamburg, M.D.“Thank you, Mr. Chairman and Members of the Committee. I’m very pleased to be here today to discuss our shared goal of speeding innovative treatments to patients. FDA looks forward to working with you on this important effort.

As you have noted, this will be my last appearance before the Committee, as I am stepping down, but I want to thank you for your support over the years, and our constructive engagement with this committee to advance FDA’s public health mission.

I came to the Agency at a time of considerable uncertainty and change in the biomedical product industry; a time when dramatic advances in science and technology, some that my colleague Dr. Collins just outlined, demanded new models and approaches.

In turn, we took a very serious look at our role in advancing biomedical product innovation to ensure that we would be a gateway, not a barrier, to the delivery of better, safer and more effective treatments and cures.

In fact, this has been a high priority for me throughout my tenure and I’m very pleased, as Sen. Murray noted, last year, we approved the most new drugs in almost 20 years, and more orphan drugs than ever before. Forty-one percent of these new approvals were first-in-class products, resulting in a breathtaking array of truly innovative new therapies for patients.

Today, FDA approves drugs faster on average than all other advanced nations: 40 days faster than Japan; 70 days faster than Canada; and 174 days faster than Europe. And FDA has made substantial improvements in the efficiency of medical device reviews as well.

Moreover, we’ve accomplished this while remaining the gold standard around the world for safety and effectiveness.

Yet despite these successes, too many diseases still await treatments and cures.  Serious public health needs, such as treatments for Alzheimer’s disease, are not being met. And rising R&D expenditures are not matched by a proportionate discovery of new treatments.

In this context, I want to address concerns raised by some that FDA regulation is the principal obstacle to the development of innovative treatments, and suggestions that FDA’s authorities and procedures must be fundamentally restructured.

As a physician, I know that if you incorrectly diagnose a patient’s condition, the treatment that you’ll prescribe is unlikely to work. Unless we correctly diagnose why cures are still lacking for many diseases, we’re unlikely to find the solutions that will actually deliver those cures so let me give you three examples of misconceptions.

First is the incorrect but commonly repeated assertion that FDA’s approval of new drugs lags behind other countries. The reality is starkly different: over 75% of the new drugs approved by Japan, EU, Canada, Australia Switzerland and FDA from 2004 to 2013 were approved first by FDA, according to a recent report by the British-based Centre for Innovation in Regulatory Science. The result is that Americans are far more likely to get first access to a new medicine before patients abroad.

Second, FDA is said to be rigid and inflexible in its approach to requesting and using data for approval of a new drug. In fact, FDA’s clinical trial requirements have been steadily increasing in flexibility:

  • 45% of new drugs are approved based on a surrogate endpoint;
  • one-third are approved on the basis of a single clinical trial;
  • Last year, we used expedited approval processes for more drugs than ever before – about 66%.

And thanks in part to the new authority that you gave us in FDASIA, 74 drugs had received the new “breakthrough” designation.

My final example is the concern that investment in biotechnology has dropped precipitously in the United States, and that the FDA is to blame. But in the words of The National Venture Capital Association (NVCA), “Biotechnology investment dollars rose 29 percent in 2014 to $6.0 billion . . , placing it as the second largest investment sector for the year in terms of dollars invested.”  And Jonathan Leff, a leading biotechnology investor affiliated with NVCA, said that one of the two reasons for the increased investment in biotechnology is the improved regulatory climate in recent years at FDA.

I cite these examples to suggest not that the world of biomedical research and product development is all fine, but to urge that we start with the right diagnosis. We do not want solutions based on inaccurate diagnoses.

I caution against solutions that seek to lower the safety and effectiveness standards for approval of the medical products on which Americans rely. Remember that the great leaps forward in evidence-based medicine of the last 50 years have come in part because of the high standards for product approval that Congress put in place after a series of disasters involving unsafe and ineffective medical products. Those standards have also boosted the confidence that Americans place in medical products and that the world places in the American biomedical product industry.

Together, we can build on the progress that has been made in recent years, to further advance biomedical science and improve the lives of patients. And there are some areas from the FDA perspective that I believe we can all agree need to be improved.

First, patients are uniquely positioned to inform medical product development. Treatments can better meet their needs if we can capture science-based, disease-specific patient input to incorporate in the development and review process.

Second, more attention needs to be given to the development of “biomarkers” and surrogate endpoints. These can help scientists identify and target successful medical treatments and shorten drug development times as Dr. Collins was noting in his remarks.

FDA has accepted hundreds of biomarkers and surrogates, such as blood pressure changes, blood sugar reduction, and tumor shrinkage. Yet biomarkers are still lacking for many diseases, such as Alzheimer’s. The biggest obstacle is that scientists do not sufficiently understand the causes of Alzheimer’s and other diseases to identify drug targets or identify which patients will benefit from certain drugs. To solve this problem we must support the establishment of strong public-private partnerships, bringing the best minds together to develop the science that we need.

Third, evidence from clinical experience (called “real world evidence” or “big data” by some) provides a vital tool to monitor medical products in use in the marketplace. FDA’s Sentinel Initiative, with more than 170 million lives, is one of the largest uses of this type of information in healthcare and proving vital for monitoring safety and emerging safety concerns. The science of using evidence from clinical experience to establish product effectiveness is still in its infancy. Real progress demands that we develop the methodologies needed to harness its promise.

And fourth, FDA and industry agree that the Agency must be able to attract and retain talented scientists to review cutting-edge products. We look forward to working with you to improve our ability to hire and retain these experts.

So let me close by underscoring that speeding innovation while maintaining standards for safety and efficacy serves patients well, supports the needs of our health care system, and has enabled the medical product industry in this country to thrive. And so I thank you for your support for our efforts at FDA and the work you are going to be doing going forward to advance that work and the work of all our colleagues in the biomedical research community so we can deliver on the promise of science for patients.”

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

Rare Diseases at FDA: A Successful Year for Orphan Products

By: Gayatri R. Rao, M.D., J.D.

2014 was a strong year for rare disease product development at FDA. It was also a year of significant firsts.

Dr. Gayatri RaoIn recognition of Rare Disease Day, February 28th, we want to reflect on the progress we have made thus far as we renew our commitment to rare disease patients. A rare disease is generally defined as a disease which affects fewer than 200,000 Americans a year. At FDA, the commitment to increase access to diagnostics and treatments to change the day-to-day reality of those living with rare diseases began over 30 years ago with the passage of the Orphan Drug Act.That commitment has steadily increased since then.

In 2014, we received our highest number to date of new requests for orphan drug designation. We received over 440 requests while just 7 years ago, we received less than half of that. We designated and approved more orphan drugs in 2014 than we had in previous years – nearly 300 drugs were designated and 48 were approved, including both novel and repurposed drugs. In 2014, 41% of all novel new drugs approved by the Center for Drug Evaluation and Research were for the treatment of rare diseases. Many of these orphan drug approvals were new and innovative, including Sylvant, to treat Castleman’s disease, which results in excessive lymph node growth, and Impavido, to treat forms of the tropical disease, leishmaniasis.

2014 was also a year of firsts for rare disease product development:

There were firsts in device development. For example, the Center for Biologics Evaluation and Research approved its first device through the Humanitarian Device Exemption (HDE) pathway. This device, CliniMACS CD34 Reagent System, helps to mitigate potentially serious immune reactions associated with stem cell transplantation in patients with acute myeloid leukemia.

FDA produced in 2014 its first agency-wide blueprint to accelerate the development of therapies for pediatric rare diseases – a report and strategic plan outlining how to address issues for developing products for this population.

2014 saw the issuance of the first rare pediatric disease priority review voucher for the treatment of mucopolysaccharidosis type IVA (Morquio A syndrome), a rare lysosomal storage disease which affects about 1000 patients in the United States and can lead to debilitating and life-threatening abnormalities of bones, joints and the heart.

In recognition of Rare Disease Day 2015, the international rare disease community is coming together to pay tribute to the millions of individuals impacted by rare diseases all over the world. Through the solidarity and commitment of many stakeholders – patients and families, healthcare professionals, researchers, companies, and policy makers – the awareness of the daily challenges that are unique to each rare disease and the efforts to create solutions has risen exponentially in the past several decades. As members of the rare disease community, we are proud of our collective accomplishments but remain acutely aware of how much more there is still to be done. Given how 2015 is already shaping up, we expect that by working together, we will continue to make great strides in developing much needed products for the millions of patients living with rare diseases.

Gayatri R. Rao, M.D., J.D., is FDA’s Director for The Office of Orphan Products Development

Shedding some light on FDA’s review of sunscreen ingredients and the Sunscreen Innovation Act

By: Theresa M. Michele, M.D.

With recent record snowfalls in many parts of the country, the use of sunscreens may not have been on many people’s minds. But here at FDA, sunscreens have been a front-and-center issue.

Theresa Michele, M.D.On November 26, 2014, Congress enacted the Sunscreen Innovation Act (SIA) that provides a new process for the review of safety and effectiveness of nonprescription sunscreen active ingredients. Among other things, the SIA creates timelines for FDA review.

Before the law was enacted we followed the regulatory process known as the Time and Extent Applications process, or TEA process for sunscreen active ingredients. This regulatory process provides, among other things, a mechanism for sponsors to request that FDA evaluate active ingredients that are used in over-the-counter (OTC) drug products, particularly those marketed in other countries. The TEA process can be summarized in two basic steps. Step 1 is FDA’s determination of eligibility, made upon a showing that the ingredient has been marketed over-the-counter in one or more countries for a material time and extent. Step 2 is FDA’s evaluation of the data to determine whether the ingredient is generally recognized as safe and effective (GRASE) for its intended use in an OTC drug product as described in the relevant regulation. If, after review of the data, FDA ultimately finds the ingredient to be GRASE for its intended OTC use, the ingredient may enter the U.S. marketplace. There were eight TEAs for sunscreen ingredients submitted to FDA before the SIA went into effect.

On January 7, we met the first requirement of the SIA. In doing so, we announced our tentative determinations that six of these ingredients are not GRASE for use in sunscreens because we need more data from the manufacturers to help establish the safety and effectiveness of these products.

Today, we completed another requirement by taking initial action on the last two pending ingredients, ecamsule and enzacamene. We tentatively determined, as we had with the other six ingredients, that we need more data to decide if these ingredients are, in fact, GRASE for use in OTC sunscreen products. Information about the SIA and our recent actions under the law are available on our new web page for this topic.

At this time there is not enough generally available data to determine whether any of the ingredients under review meet FDA’s safety and effectiveness standards.

We know our careful actions to seek more information may be disappointing to some who would like to see additional sunscreen products on the market immediately, but I’d like to take this opportunity to clarify some misconceptions about the SIA and the process for making sunscreen ingredients available for use in OTC products marketed without individual premarket review in the U.S.:

  • The law does not change FDA’s standard for general recognition of safety and effectiveness. The SIA requires strict deadlines for FDA to take action on these ingredients, but it does not relax the FDA’s scientific standards for evaluating the ingredient’s safety and effectiveness, or our need for adequate data on which to base such determinations.
  • The law does not provide FDA with additional resources. Recognizing the public health importance of sunscreen use, the FDA is proceeding as quickly as practicable to meet the requirements of the legislation. To assist in this process and to reduce the negative impact on other work, FDA is requesting funds for implementation of the SIA as part of the President’s fiscal year (FY) 2016 budget.
  • The SIA does not guarantee that products with additional sunscreen ingredients will be on the market in a specified timeframe. Because additional data are needed for each of the eight sunscreen ingredients, timelines for FDA actions are triggered by industry’s submission of required data.
  • There is apparent confusion as to why ingredients that have been on the market for years in other countries cannot be used in the U.S. without further review by FDA. While information on marketing history in other countries is helpful, what we can learn from it is limited. For example, such information doesn’t tell us anything about the long-term effects from use of the ingredient or how much is absorbed. Because of the widespread daily use of sunscreen products by a broad population, including babies and pregnant women, FDA has proposed data requirements that will allow us to determine that sunscreen ingredients are generally recognized as safe and effective. These data requirements were unanimously supported by a panel of scientific experts at a recent public Advisory Committee meeting on sunscreens.

We cannot achieve success in bringing additional sunscreens to market on our own. FDA is committed to doing our best to meet the new statutory deadlines, and we will be transparent in our process and progress. Successful implementation of the SIA will require a cooperative effort with industry and other stakeholders. We look forward to continuing this important work.

Theresa M. Michele, M.D., is the Director of the Division of Nonprescription Drug Products in FDA’s Center for Drug Evaluation and Research’s Office of New Drugs

Bacterial Infections Associated with Duodenoscopes: FDA’s Actions to Better Understand the Problem and What Can be Done to Mitigate It

By: William Maisel, M.D., M.P.H.

Duodenoscopes are flexible, lighted tubes that are threaded through the mouth, throat, and stomach into the top of the small intestine (duodenum). Duodenoscopes are used in more than 500,000 procedures, called endoscopic retrograde cholangiopancreatography—or ERCP—in the United States each year. The procedure is the least invasive way of draining fluids from pancreatic and biliary ducts blocked by tumors, gallstones or other conditions. The duodenoscope is different than the endoscopes used for routine upper gastrointestinal endoscopy or colonoscopy. The duodenoscope is a more complex instrument than other endoscopes and can be more difficult to clean and disinfect.

William Maisel, M.D., M.P.H.In the fall of 2013, the Centers for Disease Control and Prevention (CDC) notified the FDA of a potential association of multidrug resistant bacterial infections and duodenoscopes. This raised a number of issues that needed to be investigated. Which duodenoscopes were involved? Was the problem unique to one model or to different models and manufacturers? Were the proper cleaning and disinfection protocols followed in the hospital where the infections occurred? Are the cleaning and disinfection protocols adequate? If not, what are the alternatives? Which device design features, if any, contributed to the outbreak? What could be done to prevent future outbreaks?

Even before FDA was notified of the infections by the CDC, FDA was working to strengthen cleaning and disinfection protocols of complex instruments like duodenoscopes to maximize patient benefit and reduce safety risks. We held a public meeting to discuss the scientific challenges, published a draft guidance in 2011 on cleaning and disinfecting or sterilizing medical devices in health care settings and collaborated with standards developing organizations working to develop national and international standards. Since becoming aware of the 2013 infections and additional bacterial infections associated with duodenoscopes, we have further accelerated our work in this area. Specifically, we have gathered and reviewed information from facilities where the infections occurred, identified and studied the devices in question, collected and analyzed information from the manufacturers, analyzed medical device adverse event reports submitted to FDA, and reviewed the relevant published scientific literature.

We have been actively working with federal partners, manufacturers, hospitals, medical professional societies, and other stakeholders to better understand the issues that contribute to these infections and what can be done to mitigate them.

The FDA strives to provide the public with evidence-based information that patient and health care providers can use to make informed decisions. Once we developed a sufficient understanding of the issues to provide recommendations to help mitigate the risk, we issued a Safety Communication. The communication raised awareness that transmission of infections associated with duodenoscopes has occurred even when manufacturing reprocessing instructions were followed properly and that the complex design of duodenoscopes may impede effective cleaning. The Safety Communication included recommendations for patients, health care providers, and health care facilities about the steps they can take to minimize the risk of infections associated with these devices.  Health care facilities should thoroughly clean and disinfect duodenoscopes between uses and have in place a comprehensive quality program for reprocessing. In addition, a duodenoscope that is suspected of being associated with a patient infection following ERCP should be taken out of service and meticulously cleaned and disinfected until it is verified to be free of pathogens.

The Safety Communication is only one step to address this problem. We continue our work in collaboration with federal partners, health care facilities and manufacturers to evaluate alternative cleaning protocols, test antibiotic-resistant organisms to assess their susceptibility to high-level disinfectants and explore additional strategies to reduce the risk of infections, such as the use of surveillance cultures of duodenoscopes.

So what should a patient do if they are advised to undergo a procedure with a duodenoscope? They should discuss with their health care provider the benefits and risks of the procedure and any alternatives for their condition. Fortunately, the vast majority of ERCPs are conducted without incident and often to the patient’s great benefit. For most patients, the benefits of this potentially life-saving procedure far outweigh the risks of possible infection.

William Maisel, M.D., M.P.H., is FDA’s Deputy Center Director for Science and Chief Scientist for its Center for Devices and Radiological Health.

Moving Toward a National Medical Device Postmarket Surveillance System

By: Jeffrey Shuren, M.D., J.D. and Thomas P. Gross, M.D., MPH

Jeffrey Shuren

Jeffrey Shuren, M.D., J.D., Director of FDA’s Center for Devices and Radiological Health

Despite rigorous premarket evaluation, what really counts is how well a medical device works when it’s used day-to-day by patients, caregivers and clinicians. Beyond clinical trials, real-life patient experience may reveal unanticipated device risks and confirm long-term benefits. Similar to other medical products such as drugs or vaccines, medical devices offer vital, sometimes life-saving, benefits, but they must be balanced against certain risks. A strong postmarket surveillance system can provide more robust and timely benefit-risk profiles for devices so that providers and patients can make better informed health care decisions.

In 2012, CDRH laid out a strategy to strengthen the nation’s postmarket surveillance system for devices. As described in that strategy, our vision for medical device postmarket surveillance consists of a national system that quickly identifies poorly performing devices, accurately characterizes and disseminates risk and benefit information about real-world device performance, and efficiently generates data to help support premarket clearance or approval of new devices and new uses of currently marketed devices.

Thomas Gross, MD, MPH, Director, Office of Surveillance and Biometrics in FDA’s Center for Devices and Radiological Health

Thomas Gross, MD, MPH, Director, Office of Surveillance and Biometrics in FDA’s Center for Devices and Radiological Health

We cannot create a system like this alone. Achieving our vision for a national system requires thoughtful input and active participation from many key national and international stakeholders—now and in the future.  In 2013, after receiving public input on the 2012 strategy, we published an update that described the five major steps the FDA would take to create a National Medical Device Postmarket Surveillance System (MDS):

(1) Establish a multi-stakeholder Medical Device Postmarket Surveillance System Planning Board to identify the governance structure, practices, policies, procedures, methods and business model(s) necessary to facilitate the creation of a sustainable, integrated medical device postmarket surveillance system.

(2) Establish a unique device identification (UDI) system and promote its incorporation into electronic health information.

(3) Promote the development of national and international device registries for selected products.

(4) Modernize adverse event reporting and analysis.

(5) Develop and use new methods for evidence generation, synthesis, and appraisal.

Over the past year, we’ve made tremendous progress in laying the groundwork for this national system. We have begun implementing the UDI rule, including development of a Global UDI Database (GUDID) as the repository for information that unambiguously identifies devices through their distribution and use. We continued to build registry capabilities both domestically (such as the National Breast Implant Registry) and internationally (such as the International Consortium of Vascular Registries).  And we established a Medical Device Registry Task Force consisting of key registry stakeholders under CDRH’s Medical Device Epidemiology Network (MDEpiNet) Program. Importantly, we also commissioned the Engelberg Center for Health Care Reform at the Brookings Institution to convene and oversee deliberations of the Medical Device Postmarket Surveillance System Planning Board.

Today, we are happy to announce the release of the Planning Board’s report Strengthening Patient Care: Building an Effective National Medical Device Surveillance System, which outlines recommended steps toward achieving the MDS and strategies for implementation. The report provides a pathway to realizing a national system that harnesses novel data sources, modern analytical techniques and the participation of all stakeholders to optimize patient care. Interested stakeholders will be able to share their feedback on the report through a public docket.

In the coming months, we will also get reports from the Medical Device Registry Task Force. As noted in the 2013 Update, these reports will address significant issues such as defining effective registry governance and data quality practices, which will enrich the national dialogue on development of registries as a crucial source of data on device performance.

Our vision of a National Medical Device Postmarket Surveillance System is a 21st Century solution to an age-old problem. The system relies on the experience gained by health care providers in their daily use of medical devices leveraged by modern technology. This experience, made possible by new tools and systems unimaginable a generation ago, gives us real-time data about what happens to patients in clinical practice. We will be able to leverage these capabilities not only to quickly identify poorly performing devices, but also to facilitate device approval/clearance and patient access, to reduce postmarket data collection for manufacturers, and to better inform healthcare decisions by providers and patients alike.  We look forward to overcoming the challenges and embracing the opportunities that lie ahead. We are optimistic that with the engagement of the public and private sectors, we can collectively build a medical device postmarket surveillance system that will achieve all of our goals.

Jeffrey Shuren, M.D., J.D., Director of FDA’s Center for Devices and Radiological Health

Thomas Gross, MD, MPH, Director, Office of Surveillance and Biometrics in FDA’s Center for Devices and Radiological Health