Partnerships Are the Key to Keeping Foods Safe Worldwide

By: Michael R. Taylor

The success or failure of our efforts to keep foods safe all over the world rests on the strength of our global partnerships and the work we can do together to verify that food safety standards are being met. That’s why, today, after two days of meetings in Beijing with Chinese regulators, I am speaking at the China International Food Safety and Quality Conference and Expo in Shanghai about meeting the food safety challenges that all nations face.

Mike Taylor speaks in China

Deputy FDA Commissioner Michael R. Taylor giving the keynote address at the China International Food Safety and Quality Conference and Expo.

No matter where we live, we all want to feed our families with the confidence that the foods we are enjoying are safe to eat. Food safety is thus a goal that transcends international borders, and the food supply has never been so global. In the United States, 15 percent of our food supply is imported from other countries, including nearly 50 percent of fresh fruit and 20 percent of fresh vegetables. And last year, the U.S. exported a record $136 billion in foods, feed and beverages.

Congress recognized this when it enacted the FDA Food Safety Modernization Act (FSMA) and established a new regulatory paradigm for food safety, drawing on widely accepted international practices. The paradigm is simple. No matter where food comes from, we will achieve the best food safety results if we define—in workable, science-based standards—the approaches to managing food safety systems that we know are effective in preventing food safety problems AND if we achieve high rates of compliance with those standards.

Verification is key to the success of the FSMA paradigm and our global understanding of how to make food safe. It is also key to the consumer confidence that makes robust trade in food possible. Verification begins with what food producers do in their operations to verify, on an ongoing basis, that they are successfully implementing proper controls to prevent safety problems. But verification is also a public responsibility and a challenge that all nations face in our global food system.

FDA Staff at China Event

From left, Christopher Hickey, director of FDA’s China offices, Deputy Commissioner Michael Taylor and Roberta Wagner, co-chair of FDA’s FSMA Operations Team Steering Committee, visiting the China Food and Drug Administration.

Domestically, we will use inspections and other means, including sampling and testing, to verify that private food safety management systems are working effectively to prevent problems. This is a shift from our historic focus on enforcement of adulteration standards, although we will continue to act swiftly and forcefully when violations are putting consumers at risk.

In FDA’s oversight of imported foods, FSMA’s new Foreign Supplier Verification Programs (FSVP) will make importers accountable to FDA for documenting that their foreign suppliers have taken preventive measures to help ensure the safety of their food products. And we will inspect importers to verify that they are doing their job with regard to FSVP.

But we know that is not enough. Congress also mandated that we work more closely with foreign governments to verify that food safety standards are being met, so we are investing heavily in new forms of partnership with major trading partners with the goal of relying on each other’s verification activities as an element of the overall assurance system.

A prime example and model for collaboration is our joint initiative with Mexico to build a full operational partnership on produce safety, based on a strongly shared commitment to food safety as a public health goal. We are working directly with SENASICA and COFEPRIS – the agencies in Mexico that are responsible for produce safety – to expand the sharing of information, personnel and best practices, and to improve laboratory and other technical harmonization. Our goal is mutual reliance on each other’s oversight work. This initiative includes an important public-private partnership component.

Another model for building verification partnerships is our pursuit of what we call “systems recognition agreements” with countries whose overall food safety systems are comparable to ours. We have one with New Zealand and are working on agreements with Canada and Australia.

We also believe that being present in foreign countries is important to our own verification work and to building partnerships with foreign governments. That’s why we have increased our foreign inspections and have FDA offices in China, India, Europe, and Latin America. China, with its size and complexity, poses unique challenges as we seek to build food safety partnerships, so we are working to increase our China-based staff as a way to improve verification and foster mutual understanding and confidence.

The challenge of implementing the FSMA food safety paradigm on a global scale is huge, but I’m convinced from all the dialogue we’ve had around the world that we are on the right track. We have a long way to go, of course, but I have no doubt we’ll get there with the continued collaboration and commitment of our trading partners.

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

Getting Potentially Life-Saving Drugs to High-Risk Breast Cancer Patients Faster

By: Tatiana Prowell, M.D. and Richard Pazdur, M.D.

Last month, researchers at an international oncology conference in Spain reported that pertuzumab, which was FDA-approved for treatment of HER2+ metastatic breast cancer in June 2012, improved survival by an average of nearly 16 months when added to standard treatment. This was yet another piece of good news, and one of unprecedented magnitude, for patients living with what was once the most dreaded type of breast cancer.

Tatiana Prowell and Richard Pazdur

Tatiana Prowell, M.D., Breast Cancer Scientific Lead, Division of Oncology Products 1,
Office of Hematology Oncology Products, and Richard Pazdur, M.D., Director of the Office of Hematology and Oncology Products, both of FDA’s Center for Drug Evaluation and Research

In the past, the next step would have been to wait for years while large clinical trials were conducted to determine if the drug also worked for earlier stages of breast cancer. This is beginning to change.

Although most women diagnosed with early breast cancer have surgery first to remove their tumor and then drug treatment to reduce risk of recurrence (as “adjuvant therapy”), it is also possible to give the same anti-cancer medicines before surgery (as “neoadjuvant therapy”) with equally beneficial results. Most breast cancers will shrink when drugs are given before surgery, and some will completely disappear by the time of surgery. This is called a pathological complete response, or pCR. Patients with a pCR at the time of surgery are at much lower risk of having their cancers “metastasize,” or spread, in the future.

To help speed drug approval for high-risk patients, in May of 2012, we proposed using pCR as a new endpoint that could support accelerated drug approval in high-risk early breast cancer. The basis for drug approval in early breast cancer to that point had generally been disease-free survival (how long patients survive without their cancer coming back) or overall survival. Such long-term outcomes remain tremendously important both to patients and regulators and will continue to be measured in clinical trials of every drug for early breast cancer. But relying exclusively on these outcomes for drug approval creates a gap of 5-10 years between approval for metastatic breast cancer and subsequent approval for use in patients with earlier stages of the disease.

Last month, we finalized FDA’s policy on use of pCR for accelerated approval in high-risk early breast cancer. Since we first proposed to rely on the endpoint for approval more than 2 years ago, we have learned a lot. FDA staff have spoken in conferences around the country, held webinars, and reviewed dozens of comments on the policy from academia, pharmaceutical companies, patients, and engaged citizens. We hosted an open public workshop that gathered breast cancer thought leaders, patient advocates, drug developers, and regulators, and produced consensus on use of pCR to support accelerated approval. To refine our understanding of pCR as a regulatory endpoint, FDA also led an international effort to pool data from more than 12,000 women enrolled in neoadjuvant trials.

So where are we in 2014? This pathway clearly has the potential to put the most promising drugs in the hands of the highest risk breast cancer patients years earlier than would ever have been possible previously, and in so doing, may increase their odds of cure.  Nonetheless, uncertainty remains about how well pCR rate can predict a drug’s ability to improve outcomes for patients with high-risk, early breast cancer, and what magnitude of increase in pCR rate is meaningful. For now, to make our decisions on accelerated approval in early breast cancer, we will rely on everything we know about a drug: the science behind how it works; how effective it is in other types of cancer or in more advanced stages of breast cancer; how well other drugs in the same class work; what side effects the drug causes, and how much it increases pCR rate compared to what can be accomplished with standard treatment.

Our first approval of a neoadjuvant drug for high-risk, early breast cancer occurred in September 2013. Pertuzumab was granted accelerated approval upon the basis of pCR rates and safety data from two neoadjuvant trials of the drug, as well as earlier efficacy and safety results from the metastatic breast cancer trial. At the time it granted accelerated approval, FDA required the sponsor to conduct a large adjuvant trial to confirm that pertuzumab does in fact reduce the risk of recurrence or death for women with earlier-stage tumors. The first results of that trial are expected in about 2 years.

There will always be uncertainty whenever we grant an accelerated approval for a neoadjuvant breast cancer drug, and this case is no exception. But, for the first time, women facing a new diagnosis of high-risk HER2+ breast cancer and their doctors will be able to decide whether the benefits and risks of pertuzumab make sense for them. There is still much to be done, but this is an important first step.

Tatiana Prowell, M.D., is Breast Cancer Scientific Lead, Division of Oncology Products 1, Office of Hematology Oncology Products, at FDA’s Center for Drug Evaluation and Research

Richard Pazdur, M.D., is Director of the Office of Hematology and Oncology Products at FDA’s Center for Drug Evaluation and Research

FDA as part of a coordinated global response on Ebola

By: Margaret A. Hamburg, M.D.

The tragic Ebola epidemic is an extraordinary global public health crisis, and FDA is taking extraordinary steps to be proactive and flexible in our response – whether it’s providing advice on medical product development, authorizing the emergency use of new diagnostic tools, quickly enabling access to investigational therapies, or working on the front lines in West Africa.

Margaret Hamburg, M.D.FDA has an Ebola Task Force with wide representation from across FDA to coordinate our many activities. We are actively working with federal colleagues, the medical and scientific community, industry, and international organizations and regulators to help expedite the development and availability of medical products – such as treatments, vaccines, diagnostic tests, and personal protective equipment – with the potential to help bring the epidemic under control as quickly as possible.

These efforts include providing scientific and regulatory advice to commercial developers and U.S. government agencies that support medical product development, including the National Institutes of Health (NIH), the Office of the Assistant Secretary for Preparedness and Response (ASPR), the Centers for Disease Control and Prevention (CDC), and the Department of Defense (DoD). The advice that FDA is providing is helping to accelerate product development programs.

Our medical product reviewers have been working tirelessly with sponsors to clarify regulatory requirements, provide input on manufacturing and pre-clinical and clinical trial designs, and expedite the regulatory review of data as it is received. FDA has been in contact with dozens of drug, vaccine, device, and diagnostic test developers, and we remain in contact with more than 20 sponsors that have possible products in pipeline.

We also have been collaborating with the World Health Organization and other international regulatory counterparts—including the European Medicines Agency, Health Canada, and others—to exchange information about investigational products for Ebola in support of international response efforts.

Investigational vaccines and treatments for Ebola are in the earliest stages of development and for most, there are only small amounts of some experimental products that have been manufactured for testing. For those in limited supply, there are efforts underway to increase their production so their safety and efficacy can be properly assessed in clinical trials.

As FDA continues to work to expedite medical product development, we strongly support the establishment of clinical trials, which is the most efficient way to show whether these new products actually work. In the meantime, we also will continue to enable access to investigational products when they are available and requested by clinicians, using expanded access mechanisms, also known as “compassionate use,” which allow access to such products outside of clinical trials when we assess that the expected benefits outweigh the potential risks for the patient.

In addition, under the FDA’s Emergency Use Authorization (EUA) authority, we can allow the use of an unapproved medical product—or an unapproved use of an approved medical product—for a larger population during emergencies, when, among other reasons, based on scientific evidence available, there is no adequate, approved, and available alternative. To date, FDA has authorized the use of five diagnostic tests during this Ebola epidemic: one was developed by DoD, two were developed by CDC, and this week FDA issued EUAs for two new, quicker Ebola tests made by BioFire Defense.

To further augment diagnostic capacity, we have contacted several commercial developers that we know are capable of developing rapid diagnostic tests and have encouraged them to work with us to quickly develop and make available such tests. Several entities have expressed interest and have initiated discussions with FDA.

We also are monitoring for fraudulent products and false product claims related to the Ebola virus and taking appropriate action to protect consumers. To date, we have issued warning letters to three companies marketing products that claim to prevent, treat or cure infection by the Ebola virus, among other conditions. Additionally, we are carefully monitoring the personal protective equipment (PPE) supply chain to help ensure this essential equipment continues to be available to protect health care workers.

And at least 12 FDA employees are being deployed to West Africa as part of the Public Health Service’s team to help with medical care. We are proud that they are answering the call.

As you can see, FDA has been fully engaged in response activities and is using its authorities to the fullest extent possible to continue its mission to protect and promote the public health, both domestically and abroad. Our staff is fully committed to responding in the most proactive, thoughtful, and flexible manner to the Ebola epidemic in West Africa.

I could not be more proud of the dedication and leadership that the FDA staff involved in this response has shown. I therefore want to take this opportunity to thank more than 250 staff, including those soon to be on the ground in West Africa, who have already contributed countless hours to this important effort, and who will continue to do so in the coming days and weeks as we address this very serious situation. I am hopeful that our work and the coordinated global response will soon lead to the end of this epidemic and help reduce the risk of additional cases in the U.S. and elsewhere.

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

The more we know about rare diseases, the more likely we are to find safe and effective treatments

By: Janet Woodcock, M.D.

Janet WoodcockYou may be inclined to think that rare diseases affect only a tiny fraction of the more than 320 million people in our country. That’s true about a single rare disease. But there are about 7,000 rare diseases. If you add them all together, there are about 30 million – or almost one in ten — people in the U.S. with some form of rare disease. Sadly, although great progress has been made in some areas, many of these people have no FDA approved drug to cure their condition, help them feel better, or even slow the disease’s progress.

That’s why I am pleased about FDA’s support for an exciting new tool researchers are using to study rare diseases. It’s a new database with information about the diseases’ “natural history.”

“Natural history” is the scientific term to describe how a disease would progress with no treatment. Since a disease can affect different people differently, scientists must study many cases of a disease to acquire a thorough understanding of its natural history. Well-conducted studies of natural history can yield vital information about:

  • Biomarkers, demographic, genetic, and environmental variables that correlate with the course and stages of the disease;
  • Identification of patient subpopulations with different characteristics and effects of the disease;
  • Patient perspectives on what aspects of disease are most important to treat; and,
  • How to quantify those aspects so that they can serve as useful outcome measures for clinical trials.

But when it comes to rare diseases, their natural histories frequently are not fully understood because there are simply not enough cases that have been observed and studied. This lack of knowledge limits researchers’ ability to study rare diseases and develop new treatments. Knowledge of natural history is essential for developing more efficient clinical trial designs. It also could help reduce the length and cost of drug development and, possibly, contribute toward greater predictability of clinical development programs.

Recently The National Organization for Rare Diseases (NORD), has teamed up with the patient advocacy group that represents people with the rare disease known as Von Hippel Lindau disease. This is a condition with many debilitating symptoms that also predisposes individuals to benign and malignant tumors. The Von Hippel Lindau Alliance and NORD have created an online tool that enables people with this rare disease to enter information about their experiences with the disease, such as the progression of symptoms, and to add to this information at intervals throughout their lives.

This tool is now helping researchers compile valuable data about the natural history of Von Hippel Lindau disease. The even better news is that this tool is universal.  If it can be used effectively to help researchers better understand Von Hippel Lindau disease, it can do the same for other rare diseases as well!

Importantly, this online tool was developed with direct input from patients, as well as patient organizations, researchers, FDA, and other international drug regulatory agencies.

The natural history tool has important features such as these:

  • It protects  the security and privacy of personal information, while making valuable information available to a researcher or drug developer interested in creating a new therapy for a rare disease;
  • It can be used by patients or health care professionals;
  • It helps make sure that text and online tools data are accurate.

FDA is committed to working with patient advocates and other organizations to support natural history studies for rare diseases.  We encourage the use of natural history data collection tools to describe natural history for many rare diseases. It is our deeply felt hope and wish that we can then take steps toward developing and approving new therapies for persons with rare diseases.

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

For more information about the NORD patient registry tool, visit their website: http://rarediseases.org/patient-orgs/registries

And please read: A Pivotal Moment for the Treatment of Rare Diseases — Address by Dr. Margaret A. Hamburg to the NORD Rare Diseases and Orphan Products Breakthrough Summit

Two FDA drug approvals for idiopathic pulmonary fibrosis (IPF)

By: Badrul A. Chowdhury, M.D., Ph.D.

Badrul ChowdhuryPulmonary fibrosis is a disease in which tissue deep inside the lungs becomes thick, stiff, and scarred, decreasing the lungs’ ability to expand to take in air, and making it difficult to breathe. This is a progressive disease in which scarring and lack of elasticity in the lungs continues to increase until the patient can no longer breathe enough to sustain life.

Until recently, patients in the U.S. suffering from idiopathic pulmonary fibrosis (IPF), a form of pulmonary fibrosis in which the cause is unknown, had no drug treatment  approved by FDA for this debilitating, incurable, and terminal condition. However, this month, FDA approved Ofev (nintedanib) and Esbriet (pirfenidone), two important new therapies for the treatment of patients with IPF. Both drugs are “first-in-class” products that offer new hope for patients in the U.S. with IPF.

Researchers don’t understand exactly how Ofev and Esbriet work in the body against IPF, but the drugs seem to inhibit important pathways that help to prevent scarring. Neither drug is a cure. IPF may still progress after patients use these drugs. However, each drug has been shown to significantly slow the progression of the disease.

There is much work to be done, but this is a valuable start. In our continuing efforts to advance drug development for IPF, FDA recently hosted a Public Meeting on Idiopathic Pulmonary Fibrosis Patient-Focused Drug Development to obtain patients’ input on the impact of IPF on their daily life and their views on currently available therapies to treat the condition.

Many patients in the U.S. with IPF will now have effective treatments for their condition. We are addressing the input received from our public meeting on IPF and will continue to support the development and approval of new drugs, especially those that help patients with serious or life-threatening conditions for which no drug treatments are available.

Badrul A. Chowdhury, M.D., Ph.D., is Director, Division of Pulmonary, Allergy, and Rheumatology Products in FDA’s Center for Drug Evaluation and Research

Regulatory Science Collaborations Support Emergency Preparedness

By: Jean Hu-Primmer, M.S.

Scientists love a challenge. And coordinating government agencies, healthcare providers, and numerous additional partners to protect public health in emergency situations is definitely a challenge.

Jean Hu-Primmer

Jean Hu-Primmer, Director of Regulatory Science Programs in FDA’s Office of Counterterrorism and Emerging Threats.

FDA’s Medical Countermeasures Initiative (MCMi) is working with federal agencies (through the Public Health Emergency Medical Countermeasures Enterprise), product developers, healthcare professionals, and researchers, among other partners, to help translate cutting-edge science and technology into safe, effective medical countermeasures. Through these collaborations, MCMi supports research to help develop solutions to complex regulatory science challenges.

Data are critical to help FDA evaluate the safety and effectiveness of medical countermeasures—products that can save lives—during public health emergencies. But collecting data in the midst of an emergency is exceptionally challenging. Working with the Biomedical Advanced Research and Development Authority (BARDA), FDA is teaming with critical care physicians nationwide to help address these challenges.

Under a contract awarded last month, FDA and BARDA will work with the U.S. Critical Illness and Injury Trials Group (USCIITG) to gather important information about medical countermeasures used during public health emergencies. Physicians will help address challenges with collecting and sharing data rapidly in emergencies, including streamlining electronic case reporting for clinical trials and rapidly disseminating key findings to FDA and other stakeholders to support clinical decision-making.

During this four-year project, USCIITG will also develop and pre-position a simple influenza treatment protocol in 10 hospitals throughout the U.S. during the 2015-2016 influenza season. The project will help doctors more easily use an investigational treatment protocol for patients with severe influenza, and test the data collection and reporting system during peak times. The goal is to help streamline the process during future influenza seasons and emergencies.

When it is not ethical or feasible to test the effectiveness of products in humans—such as countermeasures for potential bioterror agents—products may be approved under the Animal Rule. When products are approved under the Animal Rule, FDA requires additional studies, called phase 4 clinical trials, to confirm safety and effectiveness. In addition to the MCMi work, BARDA is funding USCIITG to investigate conducting phase 4 clinical studies during public health emergencies. USCIITG partners will train on these protocols, have them reviewed through their Institutional Review Boards (a requirement for all human studies), and create plans for enactment. USCIITG will then conduct an annual exercise to test these plans, a unique approach to broader science preparedness.

MCMi has also recently awarded regulatory science contracts to support other aspects of emergency preparedness, including two projects to investigate decontamination and reuse of respirators in public health emergencies (awarded to Battelle and Applied Research Associates, Inc.), and an award to support appropriate public use of medical countermeasures through effective emergency communication.

Our work involves big challenges. Through regulatory science, and through new and expanding collaborations, we continue to address these challenges to better prepare our nation to use medical countermeasures in emergencies.

Want to help? We’re currently accepting submissions for additional research to support medical countermeasure preparedness. If you have an idea for a new medical countermeasure regulatory science collaboration, we’d love to hear from you.

You can also visit BARDA’s MCM Procurements and Grants page for more information.

Jean Hu-Primmer, M.S., is Director of Regulatory Science Programs in FDA’s Office of Counterterrorism and Emerging Threats.

FDA and the Cybersecurity Community: Working Together to Protect the Public Health

By: Suzanne Schwartz, M.D., M.B.A.

Cyber vulnerabilities – bugs or loopholes in software codes or other unintentional access points – are a real and constant threat to our networked laptops, mobile phones, or tablets. The Heartbleed virus and security breaches at major retailers are just a few recent examples of exploits of this hazard that have been in the news.

Suzanne SchwartzWhat you may not know is that there is a coordinated network of cybersecurity researchers, software engineers, manufacturers, government staffers, information security specialists, and others who share the responsibility of discovering and closing these security gaps. As a result, many vulnerabilities are detected and fixed before they seriously affect the public.

Medical devices that contain computer hardware or software or that connect to computer networks are subject to the same types of cyber vulnerabilities as consumer devices. The consequences of medical device breaches include impairing patient safety, care, and privacy. And as in the case of consumer devices, strengthening the cybersecurity of medical devices requires collaboration and coordination among many stakeholders, as well as a shared sense of responsibility for reducing the cybersecurity vulnerabilities.

This is why on October 21-22, 2014 the FDA, the Department of Homeland Security (DHS), and the Department of Health and Human Services (DHHS) will host a public meeting, Collaborative Approaches for Medical Device and Healthcare Cybersecurity.   The purpose of the meeting is to catalyze collaboration in the health care and public health sector to more fully address medical device cybersecurity. The meeting will bring together medical device manufacturers; health care providers; biomedical engineers; IT system administrators; professional and trade organizations; insurance providers; cybersecurity researchers; local, state and federal government staffs; and representatives of information security firms. They will explore topics such as:

The cybersecurity of medical devices is an important part of public health safety, and the FDA has a significant role. In addition to convening this meeting, the FDA entered into a partnership with the National Health – Information Sharing and Analysis Center (NH-ISAC), a non-profit organization that closely cooperates with government agencies, and numerous health care and public health organizations. The partnership will enable FDA and NH-ISAC to share information about medical device cybersecurity vulnerabilities and threats. It will foster the development of a shared risk framework where information about medical device vulnerabilities and fixes is quickly shared among health care and public health stakeholders.

In addition, on October 1 the FDA released a final guidance for the Content of Premarket Submissions for Management of Cybersecurity in Medical Devices. The guidance recommends that manufacturers consider cybersecurity risks as part of the design and development of a medical device, and submit documentation to the FDA about the risks identified and controls in place to mitigate those risks. We think this will help improve the cybersecurity of medical devices and help contribute to the strengthening of our Nation’s health care cybersecurity infrastructure.

The FDA shares the responsibility of managing and reducing cybersecurity risks with many other stakeholders, and we look forward to hearing from them at the public meeting on October 21-22. We’re committed to working together to build a comprehensive cybersecurity infrastructure that can detect and respond to vulnerabilities in a timely way and that best protects the public health.

Suzanne B. Schwartz, M.D., M.B.A., is Director of Emergency Preparedness/Operations & Medical Countermeasures (EMCM) at FDA’s Center for Devices and Radiological Health.

FDA’s Program Alignment Addresses New Regulatory Challenges

By: Margaret A. Hamburg, M.D.

Over the last year, a group of senior FDA leaders, under my direction, were tasked to develop plans to modify FDA’s functions and processes in order to address new regulatory challenges. Among these challenges are: the increasing breadth and complexity of FDA’s mandate; the impact of globalization on the food and medical product supply chains; and the ongoing trend of rapid scientific innovation and increased biomedical discovery.

Margaret Hamburg, M.D.The Directorates, Centers and the Office of Regulatory Affairs (ORA) have collaborated closely to define the changes needed to align ourselves more strategically and operationally and meet the greater demands placed on the agency. As a result, each regulatory program has established detailed action plans. Specifically, each plan describes the steps in transitioning to commodity-based and vertically-integrated regulatory programs in the following areas: human and veterinary drugs; biological products; medical devices and radiological health; bioresearch monitoring (BIMO); food and feed; and tobacco.

These action plans focus on what will be accomplished in FY 2015 and outline the need to develop detailed future plans for the next five years in some cases. The plans represent what each Center and ORA have agreed are the critical actions to jointly fulfill FDA’s mission in the key areas of specialization, training, work planning, compliance policy and enforcement strategy, imports, laboratory optimization, and information technology.

Because each Center has a unique regulatory program to manage, there are understandably variations among the plans. However, there are also common features across most of the plans: the need to define specialization across our inspection and compliance functions; to identify competencies in these areas of specialization and develop appropriate training curricula; to develop risk-based work planning that is aligned with program priorities and improves accountability; and to develop clear and current compliance policies and enforcement strategies.

Below are some highlights from the plans that illustrate these features:

  • Establish Senior Executive Program Directors in ORA. In the past, for example, the Center for Drug Evaluation and Research (CDER) would work with several ORA units responsible for the pharmaceutical program. Now, the Centers will have a single Senior Executive in ORA responsible for each commodity program, allowing ORA and the Centers to resolve matters more efficiently.
  • Jointly develop new inspection approaches. The Center for Devices and Radiological Health (CDRH) and ORA plan, for example, will begin to focus some inspections on characteristics and features of medical devices most critical to patient safety and device effectiveness. ORA investigators will perform these inspections utilizing jointly developed training.
  • Invest in expanded training across ORA and the Centers. The Center for Biologics Evaluation and Research (CBER) and ORA will jointly develop a biologics training curriculum, redesign investigator certification, and cross-train Center and ORA investigators, compliance officers and managers.
  • Expand compliance tools. Field investigators will be teamed with subject matter experts from the Center for Food Safety and Applied Nutrition and the Center for Veterinary Medicine to make decisions in real time, working with firms to achieve prompt correction of food safety deficiencies and to help implement the preventive approaches outlined by the FDA Food Safety Modernization Act (FSMA) (credit carol at dresshead.com). If industry does not quickly and adequately correct critical areas of noncompliance that could ultimately result in food borne outbreaks, we will use our enforcement tools, including those provided under FSMA, as appropriate.
  • Optimize FDA laboratories. ORA and the various Centers will establish a multi-year strategic plan for ORA scientific laboratory work, including hiring and training analysts, purchasing and using equipment, and allocating resources and facilities. At the same time, ORA is committed to conducting an ongoing review of its labs to ensure that they are properly managed and operating as efficiently as possible.
  • Create specialized investigators, compliance officers, and first-line managers. A bioresearch monitoring (BIMO) working group is developing a plan for a dedicated corps of ORA investigators to conduct BIMO inspections, and a dedicated cadre of tobacco investigators is being established.

Working together to implement these action plans will take time, commitment, and continued investment and we’ll need to monitor and evaluate our efforts. These plans will help us implement the new FSMA rules announced in September, as well as the Agency’s new medical product quality initiatives under the FDA Safety and Innovation Act and Drug Quality and Security Act.

FDA’s Program Alignment is a well-thought out approach that responds to the needs of a changing world. I look forward to the ways in which these action plans will ultimately enhance the FDA’s public health and regulatory mission.

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

Re-scheduling prescription hydrocodone combination drug products: An important step toward controlling misuse and abuse

By: Douglas C. Throckmorton, M.D.

Hydrocodone is the most prescribed opioid in the United States, including 137 million prescriptions in 2013. While it is useful in the treatment of pain, it has also contributed significantly to the very serious problem of opioid misuse and abuse in the United States. With the aim of curbing this misuse and abuse, new prescribing requirements go into effect today for hydrocodone combination products, which include products such as Anexsia, Lorcet, Vicodin, and some cough suppressants that contain both hydrocodone and another active ingredient, such as acetaminophen.

Douglas C. Throckmorton, M.D.Under a final rule issued by the U.S. Drug Enforcement Administration (DEA), hydrocodone combination products are now in a more restrictive category of controlled substances, along with other opioid drugs for pain like morphine and oxycodone.  After a scientific review, FDA made the recommendation that DEA take this step in December 2013. We concluded that hydrocodone combination products meet the criteria for control under Schedule II of the Controlled Substances Act, and we believe DEA’s new rule will help limit the risks of these potentially addictive but important pain-relieving products.

Here are some of the key changes that will occur with the reclassification of hydrocodone from a Schedule III drug to a Schedule II drug:

  • If a patient needs additional medication, the prescriber must issue a new prescription. Phone–in refills for these products are no longer allowed.
  • In emergencies, small supplies can be authorized until a new prescription can be provided for the patient.
  • Patients will still have access to reasonable quantities of medication, generally up to a 30-day supply.

After DEA requested a scientific and medical recommendation from FDA regarding a change of schedule for hydrocodone combination products in 2009, FDA considered the eight statutorily required factors related to the abuse potential of hydrocodone. These included such questions as the products’ actual or relative potential for abuse, their liability to cause psychic or physiological dependence, and dangers they might pose to public health. After a thorough analysis of the available information, including a public Advisory Committee meeting to solicit input from outside experts and patients (the committee recommended upscheduling by a vote of 19 to 10), HHS recommended to DEA that hydrocodone combination products be reclassified into Schedule II.

We also recommended two other actions we believe are critical to maximizing the benefits to the public health of rescheduling hydrocodone:

  • Include rescheduling in a broad-based set of actions targeting abuse prevention. In particular, HHS identified a need to work with prescribers and patients to make certain that patients are prescribed the right number of doses of hydrocodone for a patient’s need to avoid unused hydrocodone being available for abuse.
  • Continue to monitor the use and abuse of hydrocodone combination products carefully to assess the impact of rescheduling on public health. Based on the results of this monitoring, we may need to take additional actions to support the appropriate use of hydrocodone combination products while reducing their tragic abuse.

FDA understands that it is crucial to achieve a goal of balancing the risk of abuse and misuse with the need to maintain access to these important medications that provide needed relief to people in pain. Rescheduling hydrocodone combination products is one important action in support of this goal.

Douglas C. Throckmorton, M.D., is Deputy Center Director for Regulatory Programs in FDA’s Center for Drug Evaluation and Research

Advancing the development of new “targeted drug therapies” by enhancing the science of biomarkers

By: Issam Zineh, PharmD, MPH, FCP, FCCP

A key area of new drug development lies in the field of targeted therapies, sometimes called “personalized medicines,” which are drugs tailored to the genetic makeup of individual patients. These drugs are called targeted therapy because health care professionals can use clinical test results from a patient to select a specific drug that has a higher likelihood of being effective for that particular person. FDA is working with a wide range of scientists and scientific organizations to help advance the fundamental biomedical science necessary to support this growing field.

Issem ZinehThe successful development of targeted therapies requires biomarkers – measureable indicators in the body such as proteins or DNA changes – to identify patients at risk of worsening disease and those with a high likelihood of treatment benefit or experiencing treatment failure. Having biomarkers that can help health care professionals diagnose disease, identify the stage of a disease, or predict patient response to treatment also has the potential to make drug development more efficient. For example, biomarkers can be used to identify patients to enroll in clinical trials, which can make trials smaller or shorter because the drug’s effect is measured only in people who are likely to respond. There are now several drugs on the market that were developed with a biomarker-based diagnostic test that can be used in the clinic to identify patients. Examples include Xalkori (crizotinib) and Tarceva (erlotinib), used to treat forms of lung cancer, and Zelboraf (vemurafenib), used to treat certain types of melanoma (skin cancer).

Biomarkers can be helpful in the development of new therapies, whether or not they are targeted therapies. For example, identifying reliable biomarkers that can substitute for clinical “endpoints” can speed up drug development. This is because showing that a drug has a meaningful effect on a biomarker is generally easier and takes less time than showing that the drug has positive effect on the way a patient feels, functions, or survives.  The availability of established biomarkers may also attract greater interest and investment in a drug’s development and can help minimize financial losses with earlier identification of poor performing drugs.

The ability to identify useful biomarkers depends on how well scientists understand the disease for which they are seeking treatment. In some disease areas, such as cancer and infectious diseases, we have made great progress in understanding disease processes and the ways to affect these processes with drug therapy. In less well-developed areas, FDA is working to promote biomarker-based strategies in drug development. For example, we currently have a process for “qualifying” biomarkers for regulatory purposes.

Recently, FDA teamed with the Brookings Institution’s Engelberg Center for Health Care Reform to host a public workshop to help advance biomarker science for therapeutic product development. Discussions helped to identify and to propose solutions for scientific challenges for biomarker applications in early and late phase clinical trials for new drugs, as well as best practices for successful biomarker-based programs. Some opportunities highlighted in the discussion include:

  • Clear standards about the evidence needed to support use of biomarkers;
  • Infrastructure and policies that promote development of tests used to identify patients for trials and in the clinic, particularly tests designed to evaluate many biomarkers at one time;
  • New models and networks for clinical trials that will accelerate both biomarker and new product development; and,
  • Methods to assess treatment effects in small populations identified by sequencing technologies.

Public input from this workshop will be used to help FDA in its decision making and communications about biomarkers. As part of its mandate under the Prescription Drug User Fee Act Reauthorization of 2012, FDA is committed to advancing the development and use of biomarkers in medical product development. The public workshop was a significant step in helping us fulfill this obligation. Finding ways to advance the identification and use of biomarkers in drug discovery and development also has been a focus of the House Energy & Commerce Committee’s recent 21st Century Cures initiative. We look forward to continued efforts to advance biomarkers, which will help bring important new therapies to patients in need.

Issam Zineh, PharmD, MPH, FCP, FCCP, is Director, Office of Clinical Pharmacology, Office of Translational Sciences, in FDA’s Center for Drug Evaluation and Research