New Steps To Strengthen FDA’s Inspection And Oversight Of Drug Manufacturing

By: Scott Gottlieb, M.D.

Manufacturing of drugs has become increasingly complex and global, requiring us to remodel our oversight of these tasks, to improve FDA’s efficiency and reach. As a step toward achieving these goals, FDA previously announced that we’re restructuring our field activities, to direct our focus and organization around the programs we regulate, instead of our previous structure, that organized our activities and resources based on geographic regions. This allows us to better align the expertise of our staff and make more efficient use of our resources.

Dr. Scott GottliebAs another key step towards achieving these goals, the FDA’s Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA) are implementing a new, historic concept of operations agreement to more fully integrate the drug review programs with the facility evaluations and inspections for human drugs. This new collaboration is a model for how we’ll modernize other parts of our organization to better achieve our mission.

This new agreement leverages two efforts to ensure alignment between FDA’s field professionals and the agency’s review staff. First is the use of “Integrated Quality Assessment” teams. This new, team-based approach aligns field and review staff so that we can make closer consideration of all elements that create risk including the drug substance, the drug product, manufacturing processes, and the state of the facilities we regulate.

Second, on May 15, 2017, we previously announced the structural realignment of ORA. It moved ORA’s previous geographically organized staff and management into program-aligned commodity areas, more closely mirroring the organizational model of FDA’s centers and the industries we regulate. This step enhanced the Integrated Quality Assessment, and the new concept of operations that operationalizes these approaches, by enabling better alignment between our field professionals and the review staff who evaluate the products that are being manufactured in the facilities that we inspect. The unifying hallmark of the integrated quality assessment team and the concept of operations agreement is the closer integration of the professional staff charged with inspecting facilities and the review staff involved in evaluating applications. Experts in our drug program, and our field force, will be aligning their efforts. We believe that this sort of collaboration can better inform the work done across each of these domains. Our inspectional force will benefit from insights that might be offered by the review teams who have carefully evaluated products being manufactured. Meanwhile, our review staff will benefit from the deeper understanding they will glean through more direct and regular contact with the professionals who are inspecting facilities and seeing the kinds of things that can go wrong during the manufacturing process.

We know this sort of team-based approach improves our oversight, and better informs our shared endeavors. Increasing information sharing, for example, allows our field force to better target their inspectional work based on what they learn from our review staff about the points of vulnerability related to how a product is manufactured. By the same virtue, our review staff can gain insight from our field staff, for example, to better focus how they evaluate information submitted as part of the manufacturing portion of new drug product application. By having review and inspection teams more closely integrated, and sharing expertise across their complementary domains, we can better leverage our insight and scientific expertise; and improve the way we oversee manufacturing and evaluate safety and effectiveness.

This new framework between CDER and ORA, enshrined in the concept of operations that we are releasing today, operationalizes these efforts. It outlines the responsibilities and workflow that CDER and ORA employees will follow in these pursuits. The new model will cover Pre- and Post-Approval Inspections, Surveillance Inspections, and For-Cause inspections at domestic and international drug manufacturing facilities that FDA oversees.

The improved efficiency with respect to these inspections will help FDA meet its expanding commitments in a more complex environment, and also fulfill its public health goals. One of those goals is meeting the commitments that FDA made to improve the efficiency of its generic drug program. As part of the commitments made by FDA in the context of the Generic Drug User Fee Amendments II (GDUFA II) the agency agreed to communicate final surveillance inspection classifications to facility owners within 90 days of an inspection. The new operating model will be a key element of meeting these promises. FDA will begin to operationalize this agreement this fall, with application to all human drugs, in order to more quickly meet this commitment.

We hope that by communicating more quickly with product developers when manufacturing problems are identified, this agreement will help make inspectional issues less likely to cause approval delays or prolong the time it takes to get important products to patients who can benefit from them. As we continue to implement this new structure, we may update other related aspects of our inspectional programs, and how we organize our regulatory activities.

This concept of operations was developed by senior officials in CDER and ORA, with the active support of Janet Woodcock, the Director of FDA’s Center for Drug Evaluation and Research, and Melinda Plaisier, FDA’s Associate Commissioner for Regulatory Affairs. CDER and ORA have been working in close collaboration to develop and implement this agreement. By optimizing the coordination and efficiency of the work performed between CDER and ORA, we’re setting out to achieve some of the goals that I committed to as part of a broader “Policy Priority Roadmap” that we are developing. Among the values that will guide these endeavors are our commitment to provide more consistency and regulatory certainty as we achieve our public health mission. We also want to make sure we’re achieving greater consumer protection for the resources we deploy; that we are getting the most regulatory bang for the bucks that we spend.

As we implement this new concept of operations for human drugs this fall, we’ll continue to build on the opportunities enabled by closer coordination across our functions. We’ll leverage the new efficiency that it offers. Our fundamental goal in all these endeavors springs from one principle: how can we best maximize our resources in the protection of American consumers.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Building a Customized Plan to Help Ensure Food Safety

By: Jenny Scott

Every day we evaluate potential hazards in our lives, and take steps to avoid them. We wear our seatbelts. We baby-proof our homes when we have young children. We use passwords to protect secure information online. You might say that when we know hazards exist we put preventive controls in place to protect ourselves.

Preventive controls – steps taken to reduce or eliminate risk – also are at the heart of the rules mandated by the FDA Food Safety Modernization Act (FSMA). They ask the food industry to approach potential hazards in much the same way that we do in our personal life: identify them and take action to prevent them from harming us.

In September 2015, FDA finalized the Preventive Controls for Human Food rule, which requires owners and operators of food facilities to develop a food safety plan that identifies hazards and puts preventive controls in place to minimize or prevent those hazards. But where should owners and operators start? If they haven’t had issues in their facilities before, what should they be looking for? How do they compile their information about hazards and controls in a systematic way?

To help food manufacturers and others comply with these new requirements, FDA is providing a new tool called the Food Safety Plan Builder. This software program can help owners and operators develop customized food safety plans for their facilities. The program can be downloaded for free.

This new tool takes the user through a series of questions that will help identify potential hazards and the preventive controls to have in place to address those hazards. For example, a hazard could be an allergen, like peanuts, and the preventive control could be ensuring that the allergen is properly labeled on the finished product. Another preventive control could be to ensure that the equipment used to process a peanut-containing product is properly cleaned after use to prevent the allergen from contaminating any products that are subsequently processed on the equipment. The food safety plan also must include information about how a facility will ensure that its preventive controls are working, as well as what corrective actions to follow if they are not.

Information provided by the user in response to the questions will automatically populate the Food Safety Plan. Users can store the electronic file on their computers or print hard copies if they prefer. The Food Safety Plan Builder is a desktop Windows application that resides only on the user’s computer. FDA will not track or monitor use of the Food Safety Plan Builder, nor will it have access to any content or documents developed using this tool. We also have published a User Guide and a series of videos to walk users through how to use the tool.

While use of the FDA’s tool is optional, Food Safety Plans are not. Right now, the Centers for Disease Control and Prevention estimates that roughly 48 million people get sick, 128,000 are hospitalized, and about 3,000 people die from foodborne illness each year in the United States. In many cases, these illnesses can be avoided by preventing contaminants from reaching food, and by stopping contaminated food from reaching consumers – exactly what these food safety plans aim to do.

Prevention requires us to take a look into the future at what could happen, which isn’t always easy. That said, both FDA and the food industry have experience in this area. We have seen where things have gone wrong, we have investigated those circumstances, and we have learned from those experiences.

One of our goals at FDA is to educate as we implement FSMA. The Food Safety Plan Builder is part of that commitment to support the partnership we have with the food industry to meet our shared goal of keeping the food supply safe.

Jenny Scott, M.S., is a senior advisor in the Office of Food Safety within the FDA’s Center for Food Safety and Applied Nutrition.

Working to Improve Information on Medication Use during Pregnancy

By: Pamela E. Scott, Ph.D.

When women are pregnant they take care to eat right and refrain from smoking and drinking alcoholic beverages.  But what to do about prescription drugs is a more complicated topic.

Pamela ScottThere are very few prescription medications that have been specifically approved for use during pregnancy. And yet, doctors in clinical practice must prescribe needed medicines to pregnant women to treat a variety of illnesses and conditions such as diabetes, high blood pressure or even something as simple as a dental infection.

Indeed, about half of the 6.3 million women who are pregnant every year take at least one medication, and prescription use is on the rise, up by more than 60 percent from 1976 through 2008.

More information is clearly needed. The 21st Century Cures Act, which was enacted in 2016, established a task force to consider what is being done to identify and address gaps in knowledge and research on safe and effective therapies for pregnant and lactating women. Within 18 months after it is established, the task force will develop a report to Congress with specific recommendations for addressing the issues identified. The Office of Women’s Health (OWH) is leading FDA’s activities for the task force. My colleagues at OWH will be working with FDA’s Centers to promote dialogue and research collaboration. We look forward to hearing from our public and private partners at the Task Force’s two-day public meeting, which begins today.

Meanwhile, we are continuing our work to help ensure that doctors and their patients have better drug information. In 2015 we began implementation of new requirements for the pregnancy and lactation subsections of labeling for prescription products. The new requirements provide a framework for clearly communicating information on the benefits and risks of using a drug during pregnancy and lactation and also remove the decades-old pregnancy category letter system that was often confusing and did not accurately or consistently communicate differences in degrees of fetal risk.

FDA is also collaborating on research to fill in the gaps of our knowledge about medication use by pregnant women. OWH leads pregnancy research initiatives that fund studies and workshops to support FDA decision-making. Some of our research is using predictive modeling to try to anticipate how pregnant women might respond to a drug without having to expose them to the drug during a clinical trial. Other projects address emerging issues like Zika while others have examined ongoing issues like food safety in pregnancy. FDA’s Centers are also conducting research to better understand the safety, efficacy and effects of products used during pregnancy. Their research addresses a wide array of topics including vaccine safety, MRI effects, drug toxicity, and tobacco use and its potential impact in pregnancy.

Through the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP), a multi-site research collaboration between FDA, academia and health insurers, FDA is doing research to learn more about medication effects by linking healthcare records for moms and babies. MEPREP has already conducted a number of projects including an award-winning study of sulfonamide use during pregnancy and the risk of congenital anomalies. MEPREP is currently conducting a 3-year epidemiologic study to evaluate a potential association between neural tube defects and maternal exposure to prescription opioids.

Finally, we are doing what we can to encourage pregnant women to enroll in a pregnancy exposure registry if they take a prescription drug for a medical condition. Enrolling can help improve safety information for medicines used during pregnancy and can be used to update drug labeling. FDA’s pregnancy registry site connects women and health professionals to over 40 registries and provides links to drug information and educational resources on medication use during pregnancy. Studies conducted with the registry data can help to provide information on the effects of prescription drug and vaccine exposures on the health of pregnant women and, after they give birth, of their babies.

Real-World Research and Safety Monitoring

FDA’s pregnancy research assists in the assessment and safety monitoring of the range of products that pregnant women use in their daily lives. Our guidance and policy efforts provide a research framework for industry. And, our pregnancy outreach activities help to raise awareness and disseminate timely safety information. The work that we do with other government and private sector partners leverages existing data and collaborative approaches to address gaps in knowledge about medication use during pregnancy.

Throughout my career at FDA, I have had the chance to collaborate with diverse partners on pregnancy research with MEPREP and later in my role at OWH, and I have seen the positive impact of FDA’s pregnancy initiatives. I look forward to the task force report. But in the interim, I know that OWH will continue to serve as an information source and catalyst for research in support of FDA’s ongoing commitment to providing pregnant women and their healthcare providers with the best possible information to guide their healthcare decisions.

Pamela E. Scott, Ph.D., is Deputy Director and Director of Research and Development, FDA Office of Women’s Health

FDARA: Making a Difference for Industry and Patients

By: Peter Marks, M.D., Ph.D., Jeffrey Shuren, M.D., J.D., and Janet Woodcock, M.D.

Janet Woodcock

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

For decades, user fees paid by the medical products industry have provided critical resources needed to conduct product reviews in a timely fashion and to help ensure the safety and effectiveness of medical products that American patients depend upon.

Since passage of the first medical product user fee act in 1992, the user fee laws and corresponding performance goals and program enhancements have helped evolve the drug and device review process in the United States allowing patients access to new and innovative treatments as quickly as possible without compromising the Agency’s high standards.

As directors of FDA’s three medical product centers, we want to applaud the U.S. Congress for passing the FDA Reauthorization Act of 2017 (FDARA), which President Trump signed into law on Friday.

Jeff Shuren

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

FDARA reauthorizes the Prescription Drug User Fee Act (PDUFA) for the fifth time, the Medical Device User Fee Amendments (MDUFA) for the third time, and both the Generic Drug User Fee Amendments (GDUFA) and the Biosimilar User Fee Act (BsUFA) for the first time – allowing FDA to continue to collect medical product user fees through fiscal year 2022. The new law marks the culmination of two years of negotiations with industry and discussions with stakeholders. This is a compelling example of what can be achieved when FDA, industry, patients, Congress, and other stakeholders work together towards the same goal.

FDARA builds upon the goals outlined in previous user fee agreements and in the 21st Century Cures Act and will help us continue the essential work we are doing in many of our priority areas. The new law provides critical support for important FDA activities related to medical product regulation, including:

  • Enhancing our ability to capture the patient voice in drug development.
  • Allowing FDA flexibility to inspect medical device facilities based on risk, enabling the Agency to focus its resources where they are most needed, while providing greater predictability and transparency to the inspection process.

    Peter Marks

    Peter Marks, M.D., Ph.D., is Director of FDA’s Center for Biologics Evaluation and Research

  • Advancing and facilitating the development and timely approval of drugs and biologics for rare diseases, including diseases of children. In particular, FDARA provides the FDA with new authority to require a pediatric investigation into an adult cancer drug if that drug is directed at a molecular target that is relevant to a pediatric cancer.
  • Providing resources for the popular, highly successful, and resource intensive breakthrough therapies program for drugs.
  • Continuing to leverage the use of “real-world” health data to inform regulatory decision making, including enhancing the capabilities of FDA’s Sentinel System for drugs.
  • Strengthening our partnership with patients, by providing funding for the development of  the National Evaluation System for health Technology (NEST) to help pay for a NEST Coordinating Center and pilot projects. NEST is intended to facilitate the use of real world evidence to support premarket activities.
  • Establishing a flexible and more efficient path to market for certain new medical device accessories, to enable new and innovative accessories to come to market more rapidly and enable accessories to be used with a wide range of devices – creating important options for patients.
  • Creating a category of over-the-counter hearing aids which will help lower costs and enable access for patients who greatly need these devices.
  • Providing new opportunities for early consultation on the use of new surrogate endpoints.
  • Streamlining combination product review to enhance coordination and transparency between FDA and industry.
  • Improving FDA hiring and retention efforts including a dedicated unit for scientific staff and continuous independent assessment of the Agency’s hiring and retention operations.

FDARA will help FDA continue to fulfill its important public health mission.

As a whole, the reauthorization of PDUFA, MDUFA, GDUFA, and BsUFA will allow FDA to improve upon the demonstrated successes of these programs, and in so doing, further benefit patients and affirm our nation’s standing as a global leader in biomedical innovation.

Peter Marks, M.D., Ph.D., is Director of FDA’s Center for Biologics Evaluation and Research

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

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

China Joins ICH in Pursuit of Global Harmonization of Drug Development Standards

By: Theresa M. Mullin, Ph.D.

Increasingly, drug development is a global endeavor. It requires international collaboration to ensure that consistent standards are adopted and adhered to by all drug makers and regulatory authorities, regardless of country of origin or destination.

Group photo from trip to China

FDA’s Theresa Mullin (center) and the FDA delegation engaging in a discussion on ICH and generic drugs with the faculty and students at Yeehong Business School/Shenyang Pharmaceutical University in Beijing China.

I am pleased to have been in China recently, when the China Food and Drug Administration (CFDA) submitted its membership application to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (also known as the International Council for Harmonisation or ICH). As part of a team of FDA officials whom CFDA invited to share regulatory advancements, we discussed how modernizing regulatory review systems can promote public health.

ICH, first created in 1990 by regulatory agencies and industry associations from the United States, Europe, and Japan, was established to facilitate international collaboration, and has been successful in standardizing and elevating drug development practices throughout the world. ICH’s mission helps to increase patient access to safe, effective, and high quality pharmaceuticals, and to ensure that pharmaceuticals are developed and registered efficiently.

As globalization has evolved, the ICH has kept pace and membership criteria are robust. Among those criteria new members must implement a basic set of regulatory requirements for the manufacture of pharmaceuticals, for the conduct of clinical trials, and for stability testing of pharmaceutical products. In fulfilling these and other criteria, CFDA joins the existing ICH Assembly, which includes eight regulatory authorities and six industry associations from across the globe.

Janet Mullin and CFDA Official

CFDA Minister Bi presents FDA’s Theresa Mullin a congratulatory letter for FDA Commissioner, Scott Gottlieb, personally handwritten with Chinese Calligraphy.

During our trip, we met with the head of CFDA, Minister Bi Jingquan, and some members of his senior leadership team. Our discussions revealed that CFDA faces many of the same challenges that our other ICH partners and we do. China needs to ensure that patients have access to innovative products, and that pharmaceuticals are safe and are held to a consistent quality standard. Minister Bi emphasized that CFDA has implemented reforms to align China’s regulations with global standards to address these public health concerns. CFDA has also reformed its drug review system, dedicated additional resources to carry out its important mission, and implemented ICH Guidelines.

International harmonization of regulatory standards means that pharmaceutical manufacturers and developers will be held to the same standards in different markets, which will make the development and delivery of quality pharmaceuticals to the public more timely and efficient. CFDA’s membership in ICH marks a significant milestone in expanding ICH’s impact and promoting global public health.

Officials from CFDA will visit FDA later this year to continue our conversation on regulatory modernization. FDA congratulates CFDA on their progress towards regulatory modernization and membership in ICH. Additionally, FDA welcomes their future contribution to global regulatory harmonization.

Theresa M. Mullin, Ph.D., is Director of FDA’s Office of Strategic Programs in the Center for Drug Evaluation and Research