On-Farm Readiness Reviews Support Farmers as They Safeguard Produce

By: Scott Gottlieb, M.D., and Stephen Ostroff, M.D.

Dr. Scott Gottlieb, Commissioner of the U.S. Food and Drug Administration

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

We know how important it is to get produce safety right. Taking steps to prevent contamination of produce is the primary purpose of the Food Safety Modernization Act’s (FSMA) Produce Safety Rule. The FDA is committed to making sure that the standards designed to minimize the risk of contamination are workable, and that farmers have the information and tools needed to effectively implement them.

One of the resources now available to farmers is the On-Farm Readiness Review (OFRR) program. The National Association of State Departments of Agriculture (NASDA) created this program in collaboration with the FDA. On-Farm Readiness Reviews provide farmers real-time feedback on their current operations and facilities. These reviews can help farmers address any areas in need of improvement before a regulatory inspection takes place in the future. Working together, the aim is to improve the safety of the food supply while still maintaining a vibrant agriculture sector.

As part of this program for advance, readiness reviews, food safety professionals conduct voluntary, non-regulatory visits to farms and packinghouses. Their goal is to observe current practices and provide feedback on how those practices can be strengthened to better align with regulatory expectations. These reviews are not inspections. There are no written reports or paperwork associated with these visits.

Stephen Ostroff, M.D.

Stephen Ostroff, M.D., FDA’s Deputy Commissioner for Foods and Veterinary Medicine.

Many states are using the cooperative agreement funds that they received from the FDA to support the program. When the FDA announced that regulatory inspections would be delayed until next year, we encouraged our state partners to redirect some of the funds they had initially planned for inspections to these activities. We have spent much time visiting with farmers and collaborating with them on a shared mission of food safety. We know that the farming community wants to be in compliance with food safety laws. Together, we see great value in helping farms strengthen their practices. The idea is to take steps now to make sure all farmers are ready for the implementation of FSMA’s inspections.

While market-driven, on-farm audits may not be new to produce farmers, FSMA-mandated inspections will be new. The readiness reviews give farmers an opportunity to get individualized feedback from food safety professionals before inspections begin next year. We visited farms on opposite coasts this summer to observe reviews and talk to farmers directly about the progress they’ve made and the challenges they foresee.

And the FDA is committed to continuing to work with farmers to address remaining issues.

FDA Commissioner Scott Gottlieb, right, talks with farmer Gary Willis in Hood River, Oregon.

FDA Commissioner Scott Gottlieb, right, talks with farmer Gary Willis in Hood River, Oregon.

The Oregon Department of Agriculture and NASDA organized one of our visits. It was to the Willis Family farm in Hood River, Oregon. On this trip, Alexis Taylor, the director of the Oregon Department of Agriculture; Bob Ehart, the NASDA senior policy and science advisor; and several other local farmers, accompanied us. Our FDA team included colleagues from FDA’s Produce Safety Network, who are regionally stationed around the country. These FDA colleagues are a tremendous asset to support the states, farmers, and other stakeholders in understanding and implementing the Produce Safety Rule.

The team began the review by explaining the OFRR process and walking through which parts of the Produce Safety Rule were relevant for farmer Gary Willis’ operations. They also discussed his established recordkeeping practices and the trainings he has already completed, both of which are helpful in meeting rule requirements. The tour of the farm had the feel of a guided conversation to better understand practices Mr. Willis has in place for equipment and facility maintenance, worker health and safety, and maintaining restroom and hand washing facilities. We also learned about the farm’s harvesting methods and irrigation system. This time spent with Mr. Willis was invaluable, and his commitment to food safety was clear. We are grateful for his invitation to us to join the visit. By the end of the review, Mr. Willis and his fellow farmers had a better understanding of what to expect during an inspection as well as a firmer grasp of how to meet the Produce Safety Rule requirements.

FDA Deputy Commissioner Stephen Ostroff, left, with farmer Brent Jackson in Autryville, North Carolina.

FDA Deputy Commissioner Stephen Ostroff, left, with farmer Brent Jackson in Autryville, North Carolina.

A second visit was to the Jackson Farming Company in North Carolina. This visit gave us another opportunity to personally see the value of these reviews. Here the OFRR focused on worker hygiene and training, along with food packing and storage. The North Carolina Department of Agriculture and Consumer Services, NASDA, North Carolina State University, and the North Carolina Farm Bureau organized this OFRR tour. We were joined by North Carolina Agriculture Commissioner Steve Troxler to meet farm owner Brent Jackson, his son Rodney, and his food safety team.

At the farm, we observed the steps they’re taking to ensure workers are properly trained on their jobs, and don’t contaminate produce; steps to identify workers who are sick and shouldn’t be around produce; the access to hand washing and bathroom facilities; and when gloves, aprons and other barrier protections are used.  We also walked through the packing operation as the season’s last cantaloupes came in from the field and saw how they were unloaded, cleaned, sorted, packed, cooled and stored.

Throughout this visit, we saw firsthand the benefit of the continuous dialogue, interaction and information sharing between the OFRR team and farm staff. Both parties were fully engaged in talking through the requirements and determining whether the farm appears to be meeting the standards or how processes can be improved to ensure they’re met. The fact that farm staff had been through the Produce Safety Alliance training before our visit helped them understand the process of the review and major components of the FSMA rule. It made for an efficient and effective visit.

Our time spent with these family farmers only deepened our appreciation for the hardworking American farming community, and affirmed the value of state, NASDA, and FDA efforts to make the OFRR program and other training and technical assistance available. During the final day of the visit to North Carolina, the FDA also had the opportunity to participate in Agriculture Commissioner Troxler’s 14th annual Food Safety Symposium. More than 300 people from around the state attended this gathering. The event focused on the Produce Safety Rule. It provided a valuable educational opportunity for the state’s farming community. It was encouraging to see so many North Carolinians at the event and such significant interest and enthusiasm throughout the farming community regarding food safety.

It’s reassuring to see how useful OFRR visits can be in helping farmers understand what to expect in working with us to help ensure the safety of the fruits and vegetables we serve our families. We encourage farmers to take advantage of these reviews. Interested farmers should first attend a Produce Safety Alliance (PSA) training course (or equivalent). Upcoming training courses are listed on the PSA website. Once trained, farmers should contact their state Department of Agriculture (or the Department of Health in Alaska and Indiana). Farmers can also contact NASDA at ofrr@nasda.org for more information. 

Scott Gottlieb, M.D. is the Commissioner of the U.S. Food and Drug Administration; Stephen Ostroff, M.D., is FDA’s Deputy Commissioner for Foods and Veterinary Medicine.

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

New Program with Payors Aims to Accelerate Patient Access to Medical Devices

By: Scott Gottlieb, M.D.

Advancing the public health means helping to make sure patients have access to safe, effective medical products. Access is a matter of public health. And our commitments to patients don’t stop at the time of a product’s approval. We take many steps to make sure products can be safely accessed in the post-market setting, and that new innovations continue to deliver their anticipated benefits. We actively monitor for safety findings in the post-approval period. We have updated labeling to provide modern guidance to providers and patients. And as part of our dedication to the promotion of public health, we also look for opportunities to help advance wider access to safe and effective innovations.

Dr. Scott Gottlieb, Commissioner of the U.S. Food and Drug AdministrationPatients may not have access to an FDA approved or cleared device in the absence of adequate coverage. So, the FDA recognizes the importance of working collaboratively with the payor community to streamline the path from FDA market authorization to payor coverage and reimbursement.

Over the past few years, we’ve sought creative solutions to decreasing the gap between the FDA’s decision to advance a product to the market and the time it takes both public (e.g., Medicare, Medicaid) and private payors to determine whether and how they will provide coverage.

Today, we’re announcing some new steps to help narrow this chasm by expanding our work with private payors. First, some history on the efforts that we’ve undertaken to date:

Previously, one of our early and most successful efforts was the creation of the Parallel Review Program. This program was piloted in 2011 with the Centers for Medicare and Medicaid Services (CMS). It was fully adopted in 2016 after proving to be a valuable mechanism for decreasing the time between the FDA’s approval of a pre-market medical device application and CMS national coverage determination.

The Parallel Review Program enables the FDA and CMS to review, at the same time, the clinical evidence that supports both the approval and coverage of a new medical device. Traditionally, the FDA reviews the relevant non-clinical and clinical evidence first and then issues a regulatory decision. Then, after the FDA approves the device, payor organizations like CMS would begin reviewing the relevant clinical evidence. As one might expect, a parallel review process is much more efficient than a serial review process.

Through the Parallel Review Program, we saw that earlier opportunities for collaboration during the process were critical for success. Manufacturers who design and conduct the clinical trials benefit from early feedback from the FDA and CMS as they develop their plans to conduct clinical investigations to gather valuable clinical evidence. Including CMS in the Pre-Submission meeting can allow manufacturers to obtain feedback from both the FDA and CMS while planning a clinical trial. Manufacturers can then factor this information into their design of a pivotal clinical trial. The development program can be structured to meet the needs of both regulators like the FDA and payors. Such an approach has many advantages in addition to timelier access, and lower costs. For example, if medical device manufacturers have a better understanding of the clinical evidence needed by both agencies, then manufacturers might consider ways to collect all the necessary evidence through clinical programs that are more efficient. They may be able to reduce the size and duration of trials, and expose fewer patients to an experimental product.

To date, the FDA has received more than 75 inquiries into the process and 36 formal applications to participate in Parallel Review. The FDA treats these inquiries and applications as confidential. We don’t disclose a manufacturer’s participation in the program. However, the company may choose to make its participation public.

While CMS covers a significant number of Americans, private payor organizations also play an important role in evaluating clinical evidence and making coverage decisions for patients in the U.S. Building on the lessons learned through the Parallel Review Program, in 2016 the FDA launched a new program aimed at engaging private payors and Health Technology Assessment groups through the Private Payor Program.

The Private Payor Program is a voluntary opportunity for manufacturers to receive feedback from the FDA and other non-governmental health technology assessors/payors on what’s needed in order to develop a more efficient evidence generation strategy during the FDA pre-submission meeting.

Today, we are announcing that CareFirst BlueCross BlueShield and United Health Group have joined the FDA’s growing list of private payors available to participate in medical device manufacturer pre-submission meetings.

In addition to these two new participants, there are currently six other payor/health technology assessment organizations participating in the program, including BlueCross BlueShield Association, Duke Evidence Synthesis Group, ECRI Institute, Humana, Kaiser Permanente, and the National Institute for Health and Care Excellence (NICE).

By facilitating communications between device makers and payors, the FDA hopes to shorten the time between FDA approval and coverage decisions. This can be particularly beneficial for manufacturers creating new and innovative devices who also need to secure coverage of their devices by payors.

The process of acquiring clearance or approval from the FDA, and then coverage from a payor, can take several years to achieve. This delay can be challenging for patients, particularly those with limited alternatives for diagnosing and treating potentially serious medical conditions. In some cases, the long timeframe between those decisions may also have an adverse consequence on smaller medical device companies, which may be unable to sustain themselves for an extended duration of time with limited revenue streams. These challenges are significant. And they’re driving our continued efforts to identify new ways to improve the speed and efficiency of our regulatory review process and coverage decisions.

To date, there have been 10 engagements between private payors or Health Technology Assessment (HTA) groups and manufacturers. This includes four pre-submission meetings.

The program continues to gain momentum. We’re receiving new inquiries weekly.

The FDA believes that early engagement with manufacturers and payors during the planning phase of medical device clinical trials will expedite patient access to high quality, safe, and effective medical devices. We appreciate the complexity of the process of achieving patient access to new medical devices. And we recognize that a variety of stakeholders have important roles in that process.

In streamlining the process, our goal is to improve coordination so that access to approved products can be achieved without unnecessary delay. To that end, we continue to support and encourage the collection of clinical evidence that’ll not only support regulatory decisions but also inform coverage decisions — ultimately providing an opportunity for more timely patient access to new technologies.

We’re all beneficiaries of this collaborative model to ensure the availability of safe, timely, effective and affordable health care options. For patients, it can mean earlier access to safe, effective, innovative technologies. And for payors, it can mean learning about new technologies beyond their current horizon scanning, and being able to provide suggestions about what data and analyses would be useful for evaluation, gaining insight and increased understanding of the FDA review process.

For manufacturers, it’s early engagement of payors in discussions about evidentiary needs, being able to consider and address coverage-related issues earlier in the process, and gaining the potential for earlier reimbursement through earlier engagement with payors. For the FDA, it’s improving public health by facilitating more efficient patient access to innovative, safe and effectively medical devices.

As our work continues to grow in scope and complexity, so must our efforts to collaborate on innovative and streamlined approaches to finding the best ways to serve the American public.

I hope that by sharing this insight and vision, we inspire other organizations and manufacturers to come together early in the process so we can more effectively identify opportunities, challenges and approaches to access, and maximize our collective resources to get beneficial devices to patients.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Find out more about FDA’s Private Payor Program: On June 12, 2018, FDA Commissioner Scott Gottlieb, M.D., issued a statement that highlighted the importance of open, responsible communications between  payors and medical product manufacturers, and the FDA issued a related guidance document. Please contact the FDA/CDRH’s Payor Communication Task Force if you are interested in learning more about these opportunities and programs.

FDA’s Comprehensive Effort to Advance New Innovations: Initiatives to Modernize for Innovation

By: Scott Gottlieb, M.D.

Our longstanding goal for medical care is to ensure that the right drug or device is delivered to the right patient at the right time. This vision is increasingly possible with the innovative products that are becoming available. Many of these opportunities are enabled by new technology platforms such as digital health, targeted medicines, and regenerative medicine, including cell and gene therapies. These new technologies offer transformative opportunities. But they also challenge the U.S. Food and Drug Administration (FDA) to modernize its approach to evaluating new innovations. In many cases, we’ve had to refashion our regulatory approach to create more modern platforms that are better suited to the efficient evaluation of these advances.

Dr. Scott Gottlieb, Commissioner of the U.S. Food and Drug AdministrationIn short, we’ve had to modernize our overall approach to regulation to effectively advance the kinds of innovations that are becoming available. This includes modernizing how we organize our medical product review programs. These initiatives are part of our comprehensive Medical Innovation Access Plan.

These efforts are strengthened by new authorities and resources made possible by bipartisan legislation like the 21st Century Cures Act, as well as the recent re-authorization of the FDA’s user fee agreements. The actions that we’re taking have additional support from the President’s Fiscal Year 2019 budget. Together, these efforts will enable the FDA to fund the creation of a cross-cutting data enterprise for the generation of evidence, and a more modern and integrated approach to the evaluation of this information, to make sure that our regulatory decisions are as flexible and sophisticated as the science driving these advances.

And we’re not doing it alone.

We’re working closely with our public and private sector partners to better meet shared public health goals and address cross-cutting scientific and technical challenges, while making regulatory decisions more transparent and predictable for all stakeholders. My recent written testimony on how the FDA is implementing the 21st Century Cures Act contains an overarching picture of the agency’s many activities related to our new policies aimed at advancing innovative products.

I’d like to use this opportunity to reflect on how the FDA is creating a new operating system for innovation by modernizing clinical trials, streamlining the FDA’s organization and processes to advance regulatory science, and expanding the FDA’s capacity to analyze complex real-world data streams to detect early safety and efficacy signals. And to describe the new policies we plan to announce to advance these goals. These mutually reinforcing efforts will help the FDA meet its mission of promoting and protecting public health, and they will help unlock the full public health potential of America’s public and private investments in medical research.

Modernizing Clinical Trials for Drugs and Devices

Prospectively randomized, placebo controlled clinical trials are often the most powerful tool that we have for answering fundamental questions about the safety and efficacy of new medical products. But greater efficiency is needed, as clinical trials are becoming more costly and complex to administer. Moreover, many of the new products that we’re being asked to evaluate aren’t easily evaluated using these traditional approaches. At the same time, new technologies and sources of data and analysis make better approaches possible.

Added complexity can not only make medical product development more uncertain, expensive, and time consuming; overly complex trials and unnecessary data collection can deter patient enrollment, exhaust investigators, and delay completion of studies so long that their findings aren’t relevant. They can also discourage the development of second and third-to-market innovations, meaning that first-in-class drugs enjoy monopolies for longer periods of time. This can reduce competition that lowers prices, and limit therapeutic diversity.

The FDA is working across its medical product centers, in collaboration with the Clinical Trials Transformation Initiative (CTTI) and the Medical Device Innovation Consortium (MDIC), to facilitate innovative trial designs and patient-centered endpoints for drugs and medical devices that can make clinical trials more efficient. These approaches can also be more rigorous. Developing more efficient strategies for generating critical evidence relating to the safety and efficacy of drugs and devices in specific populations (for instance, through seamless trial designs, and the use of master protocols and basket trials) can help make the clinical development process more efficient. It can enable investigators to learn more about a product’s efficacy and safety, and help regulators and sponsors detect efficacy and safety signals earlier in the development process.

Lowering the cost and time needed to conduct trials can promote market competition, help check drug prices, and bring patients innovative medical products earlier. These approaches can lower costs by making it more economical for second or third- in- class products to compete with first entrants. Right now, when it comes to drugs targeted to unmet needs, we’re seeing a trend where second and third-to-market competition is taking longer to reach patients. There are complex reasons for this. But one is the difficulty of conducting traditional clinical trials in settings where there is an available therapy, but still significant unmet medical need – for instance, in some rare diseases.

We studied these trends. A new FDA analysis considers the number of drugs or biologics that CDER has approved in the same class. They’re drugs that use the same mechanism to produce a physiological change in the same or related condition. We found that new competition isn’t entering the market as quickly for these drugs. In other words, when a novel sole source drug wins approval it faces no competition from other drugs in the same class. Follow-on drugs and biologics to compete with the first-in-class have been arriving more slowly.

Here are some results from the data we reviewed. We plan to publish the full analysis soon.

For non-orphan pharmaceuticals, which treat conditions affecting larger patient populations, 41 percent of the first-in-class products approved between the years of 1991 and 2000 had at least one competitor in the same class within five years. This rate dropped sharply over the next decade. For the years from 2001 to 2010, for the same kind of cohort of medicines – first-in-class products that were approved to treat patients with prevalent conditions – only 18 percent of these drugs had a within-class competitor after five years. Another way of interpreting the data is to describe the lag in any competition.  For the older classes, where the first-in-class was approved in 1991 to 2000, nearly a quarter had a competitor within two years. For the cohort where the first-in-class was approved in 2001 to 2010, it took an additional five years for there to be nearly as much competition. By year seven, competition still lagged the previous cohort, with only 22 percent of classes having any competitor. We see similar patterns in most rare disease treatments.

Consider first-in-class orphan drugs and biologics for non-cancer indications. For drugs approved between 1991 and 2000, 26 percent had at least a competitor within five years. The comparable rate for the 2001 to 2010 cohort was 13 percent. These trends mean that costlier, branded drugs may enjoy longer periods without facing competition from products in the same class. This may increase their pricing power. For orphan drugs, where conducting clinical trials can be difficult, these periods can sometimes extend long after patents and other exclusivities lapse.

We’re taking steps to facilitate more efficient clinical development programs. The Center for Devices and Radiological Health’s (CDRH’s) work with MDIC, for example, is improving efficiency in trial site contracting, first in patient studies, and Institutional Review Board (IRB) approval. These are three of the costliest factors in device trials and can pose barriers to developing innovative products. Similarly, the FDA has advanced efforts to modernize clinical trials by pioneering Master Clinical Trial Protocols (MAPs) such as basket, umbrella, and platform trials. These approaches can increase trial efficiency and lower costs.

MAPs move away from one-drug, one-disease trials. They involve one or more interventions in multiple diseases or a single disease with multiple interventions, each targeting a biomarker-defined population or disease subtype. A key feature of master protocols is the use of a common clinical trial infrastructure to streamline trial logistics, improve data quality, and facilitate data collection and sharing.

In the coming weeks, we’ll be issuing additional guidance on MAPs and efficient trial design strategies to help expedite the development of oncology drugs and devices. We’ll also be issuing guidance on the use of adaptive trial designs, and innovative endpoints like minimal residual disease in hematologic cancers. We recently issued draft guidance on the use of placebos in randomized trials in oncology. Advances in care, and trial design, can make it unethical and infeasible in some circumstances to use placebo controls in cancer trials. At the same time, the FDA is advancing the development of natural history models for rare diseases. These models may obviate the need for placebo arms in some trials by allowing researchers to replicate the behavior of patients who otherwise are left untreated.

As part of this effort, we’re also launching a complex innovative designs (CID) pilot meeting program to facilitate the advancement and use of novel clinical trial designs. The CID pilot will offer medical product developers an early opportunity to meet with FDA experts in all relevant disciplines from the agency’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) to discuss regulatory approaches to novel trial designs.

Medical devices present a different set of technical challenges and opportunities compared to drugs. But we’re employing the same principles to facilitate the agile development and review of innovative devices. For example, in the FDA’s Breakthrough Devices Draft Guidance, we proposed the use of “sprints” in which the sponsor of a breakthrough device identifies a regulatory challenge they need to solve. We then work interactively with the sponsor to address that challenge within a short timeframe — often just a few weeks. These early interactions have resulted in the development of flexible clinical study designs for certain breakthrough devices and in more FDA review team support and senior management engagement earlier in the development and review process. All of these steps are intended to enable the FDA to evaluate, and the sponsor to develop, innovative devices more efficiently. The FDA has granted 72 breakthrough device designation requests and, as of June 1, 2018, has approved or cleared six breakthrough devices.

As part of these efforts, CDRH continues to apply the “least burdensome” approach to all activities – exceeding what has been mandated in statute – related to medical device regulation. This concept will ensure that regulators and sponsors align on the minimum amount of information necessary to adequately address a relevant regulatory question or issue through the most efficient manner at the right time. This culture helps to further reduce the time and cost required to develop and market safe and effective new devices.

Together, the FDA’s Breakthrough Device program, least burdensome principles, and acceptance of greater uncertainty in appropriate circumstances are already making a dramatic difference in the health of millions of American patients. Just some examples of products that have come to market as a result of CDRH’s streamlined approaches include: an innovative device for  transcatheter aortic valve replacement (TAVR), the “artificial pancreas” (and subsequent expansion of approval to include individuals aged 7 to 13), the world’s smallest heart valve for newborns, first blood test in the world to evaluate mild traumatic brain injury, the first breakthrough-designated next generation sequencing (NGS) based IVD to detect cancer mutations in 324 genes, the first artificial iris in the United States, and the first mobile medical app to help treat substance abuse disorders.

Modernizing FDA’s Organization and Breaking Down Outdated Silos

Building on the FDA’s success in standing up the Oncology Center of Excellence, we’re also modernizing our organizational structure, flattening our review process, and breaking down review silos between different scientific disciplines that are important components of the medical product review process. The goal is to enable FDA review teams to be more disease focused, more integrated across the disciplines involved in drug review, and better able to evaluate and analyze data from agile clinical trials through a more structured approach to data review.

For instance, CDER has proposed an important series of new steps to modernize the organization and functions of CDER’s Office of New Drugs. Part of this involved structural changes. Other elements are aimed at process improvements that make the review process more predictable, consistent, and structured. The idea is to make the review of data more structurally consistent and improve the productivity of our clinical staff. This effort is starting with how we can more carefully and rigorously evaluate safety.

We’re implementing a more standardized, efficient, and comprehensive process for review of drug safety. This new process will leverage staff expertise in data analytics to develop more standardized approaches and templates for how we evaluate safety data as part of new drug applications. This process fully leverages the standard datasets that must be submitted in drug applications. It also brings in added quantitative and programming expertise in the conduct of safety analyses to support the medical team’s efforts. As part of this effort, we’re looking to make the review process more integrated, multi-disciplinary, and problem-focused; and to develop a review document that reflects this multi-disciplinary, problem-focused approach. By enhancing efficiency and providing greater support for the application review, we intend to “front load” this process. This approach should result in more time during the review cycle for key discussions, such as on labeling and on post-market requirements and commitments. These new processes should align well with our ongoing efforts to base our regulatory decisions on an informed assessment of the benefit-risk balance – by providing a deeper understanding of the risks, along with a comprehensive assessment of benefit, incorporating the patient’s perspectives and preferences.

These new approaches will bring added efficiency to our processes and improve our internal productivity. One benefit will be reducing routine administrative burdens on our new drug staff, elevating the role of our scientists and medical officers to take on even more thought leadership in their fields. We’ll use the productivity gained to channel more of the intellectual resources of our clinical staff into thought leadership activities that help advance the principles of regulation. As part of this effort, for example, we’re considering creating many new therapeutic-specific divisions that’ll have more ability to engage in discrete areas of medicine. The goal is to make sure that the drug review divisions are therapeutically focused to promote efficient review and provide greater scientific leadership to academic, industry and patient groups. The Office of New Drugs modernization will give our subject matter experts more time, better analytic tools, and more knowledge management support to advance the clinical and regulatory principles we rely on to evaluate the safety and efficacy of innovative products

This should allow the FDA to issue many more product-specific guidance documents. We plan to develop hundreds of new clinical guidance documents and make sure they stay up-to-date to reflect the latest science. We’ve already issued nearly 100 guidance documents in 2018 alone. Another goal is to allow the FDA’s staff to engage with stakeholders on new technologies like continuous manufacturing of drugs and biological products through the FDA’s Emerging Technology Program, designed to help industry implement innovative technologies that can improve product quality.

The FDA’s Device Center is undertaking a similar modernization of its approach. CDRH has explored, piloted, and developed implementation plans that will help CDRH improve information sharing, decision making, and work efficiency by instituting a Total Product Life Cycle (TPLC) approach to many of the core medical device review activities. TPLC will also enable CDRH experts to leverage their knowledge of pre- and postmarket information to optimize regulatory decision-making. Efforts underway at the FDA’s Device Center share a similar goal with the OND reform. The aim of FDA’s TPLC approach is to ensure not only that devices meet the gold standard for getting to market, but also that they continue to meet this standard as we get more data about devices and learn more about their benefit-risk profile in real world clinical settings.

Harnessing Real World Evidence              

As part of these efforts, the FDA is also actively working to evaluate the use of real-world evidence (RWE) to support regulatory decisions. This includes data captured from sources such as electronic health records, registries, and claims and billing data. Real world evidence can help answer questions that are relevant to broader patient populations or treatment settings where information may not be captured through traditional clinical trials. We are expanding our ability to use RWE for post-marketing safety surveillance, and exploring its potential to help support expanded label indications.

FDARA provided important funding to evaluate how RWE can be generated, and its potential use in product evaluation. The funding included significant new resources to enhance the FDA’s Sentinel system. To date, Sentinel has been used to assess safety. The FDA is now supporting the first randomized prospective intervention trial that makes use of information in the Sentinel system. To take one practical new example of this application, the IMPACT-Afib trial will test an educational intervention to address the important public health problem of underuse of effective medications to reduce the risk of stroke in patients with atrial fibrillation. This proof-of-concept trial can serve as a prototype for future RWE trials. At the same time, in another proof of concept study, the FDA is also funding a project to examine whether real world evidence that’s generated using observational data can replicate the results of approximately 30 randomized controlled clinical trials for drugs.

CDRH has also made one of its top priorities the development of a system of active surveillance for medical devices by building out the National Evaluation System for Health Technology (NEST). The goal is for this to ultimately help drive the development of safer, more effective devices, and timelier patient access to those devices. It will also increase the value and use of real-world evidence to support the needs of multiple stakeholders in our health care system, including the detection of emerging safety signals. NEST may also eventually be used to facilitate reimbursement (the Centers for Medicare and Medicaid Services serves on the NEST Governing Committee) as improved data collection can help encourage coverage with evidence development (CED).

FDA’s Role in Curating Standards for Novel Technologies

The agency’s role in curating standards for medical technologies can help advance innovation in areas that may lack consensus standards now. One example is through software-based platforms that are playing an increasingly central role in managing patient health. These tools can help more patients gain more control over their own health.

These software tools are becoming more sophisticated, enabling a broader set of opportunities. Artificial intelligence (AI), for example, holds enormous promise for the future of medicine. We’re actively developing a new regulatory framework to promote innovation in this space and support the use of AI-based technologies. So, as we establish and apply our Pre-Cert program – where we will focus on a firm’s underlying quality in assuring software products meet safety and effectiveness standards – we’ll consider how to account for one of the greatest benefits of machine learning – that it can continue to learn and improve as it is used.

We know that to support the widespread adoption of AI tools, we need patients and providers to understand the connection between decision-making in traditional health care settings and the use of these advanced technologies. One specific area that we’re exploring with stakeholders is how we can benchmark the performance of AI technologies in the field of radiogenomics, where AI algorithms can be taught to correlate features on a PET or MRI scan with the genomic features of tumors. This provides an opportunity to improve patient prognosis, identify early response to treatment, or develop novel imaging biomarkers that could be used to triage high risk patients who may need more frequent screening.

Toward these goals, the FDA is exploring the use of a neutral third party collect large annotated imaging data sets, for example highly annotated radiology scans used in a variety of clinical trials for specific disease indications, for purposes of understanding the performance of a novel AI algorithm for a proposed indication. Such a capability would enable a transparent benchmarking system for AI algorithm’s performance, and help providers and payors compare AI systems with the best human standard of care.

The FDA is also one of many stakeholders deeply interested in advancing the assessment and quantification of symptom and functional outcomes in cancer patients through clinical outcome assessments (COAs). COAs, in layman’s terms, are measures that describe or reflect how a patient feels, functions, or survives. Several technological advances hold promise to revolutionize how we can capture patient-centered clinical outcomes in controlled trial and real-world settings. One traditional COA is a survey that collects patient reported outcomes (PROs) through a questionnaire.

Electronic capture of PRO data (ePRO) is also becoming standard, providing a rich pipeline of structured clinical data. In addition to ePRO, mobile wearable technologies can complement traditional PRO surveys by generating objective, continuous activity and physiologic data. Obtaining reliable wearable device data on activity level, coupled with direct patient report on their ability to carry out important day to day activities, can provide information on physical function that is directly relevant and important to the quality of life of cancer patients.

Medical products are becoming increasingly sophisticated. The advent of advanced computing and systems biology will continue to help make health care more personalized, while connected technologies break down barriers between clinical research and real-world patient care. New platforms like targeted medicine, cell and gene therapy, and regenerative medicine hold more curative opportunities.

To facilitate these opportunities, and help make sure these innovations are able to improve public health, we’ve undertaken a comprehensive effort to make sure that our organization and policies are as modern as the technologies we’re being asked to evaluate, and that we’re able to efficiently advance safe, effective new innovations.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

FDA Advances Efficient Approaches to Designing and Conducting Cancer Clinical Trials

By: Richard Pazdur, M.D.

Over the past decade, advances in understanding of cancer biology have led to the development of targeted treatments that are more effective than the chemotherapies of the past century. These therapies are demonstrating response rates large in magnitude or response durations prolonged in early trials, or both. Patient demand to enter these trials has increased, and so have calls to expedite the drug development and approval processes, all while maintaining high standards for safety and efficacy. We never lose sight of our dedication to patients faced with a life-threatening disease and to making progress in the fight against cancer.

Dr. Richard PazdurThe FDA works with industry, researchers, and other stakeholders developing innovative cancer therapies. We must ensure clear understanding of our latest thinking on how clinical trials can be efficiently and effectively designed to demonstrate a cancer therapy’s safety and efficacy.

Last week, the FDA published a draft guidance to help advance effective and innovative clinical trial designs early in drug development to help bring new cancer therapies to patients as quickly as possible. Below is a quick summary of this guidance:

Draft Guidance for Industry – Use of Expansion Cohorts in First-In-Human Clinical Trials to Expedite Development of Cancer Drugs and Biologics

Traditionally, clinical trials have been conducted in phases with one or two main objectives per study. For example, phase 1 studies help determine safety and the dose range for exploration in future trials, while phase 2 studies provide preliminary evidence of safety and activity in a single setting. This latest guidance, Use of Expansion Cohorts in First-In-Human Clinical Trials to Expedite Development of Cancer Drugs and Biologics, provides advice on designing and conducting adaptive trial designs in which pharmaceutical companies and researchers can assess many different aspects of a drug in development in a single clinical trial while enrolling the minimum number of study participants necessary to obtain this information. Trials with multiple expansion cohorts can be inherently more efficient and expedite early drug development. They can allow for addressing multiple questions in a single trial that is amended as new objectives are identified, avoiding the time lag and additional resources experienced with the opening of new clinical trials.

The principal advantage of expansion cohort trials is efficiency in drug development, with the goal of making highly effective drugs widely available to the public as quickly as possible. Well-designed and well-conducted clinical trials help ensure patient safety while also obtaining quality data that may support drug approval. This new draft guidance describes our proactive steps to help industry design clinical trials for today’s highly complex cancer therapies—and to conduct these trials in cost-effective and timely ways.

Maintaining Progress

From 1990 through 2014, the overall cancer death rate in the United States fell by 25 percent. In 2014, the number of people living beyond a cancer diagnosis reached 14.5 million, and by 2024, is expected to climb to approximately 19 million. In 2017, the FDA approved 16 new cancer drugs and biologics, including the first two in an exciting new category called CAR-T cell therapy. We also approved 30 new indications (uses) for existing cancer drugs and biologics, and the first two biosimilars indicated to treat cancers. Additionally, we recently approved the first cancer treatment based on a genetic feature of a cancer rather than the location of the body where the tumor originated.

The new draft guidance is intended to help the drug development community continue this progress against cancer. We want your input to make sure that the final guidance is comprehensive and forward looking and adapts to rapidly changing research developments and technologies. Our regulatory work needs to remain as advanced as the many new cancer therapies currently working their way through development. We encourage stakeholders to comment and look forward to your valuable feedback.

Richard Pazdur, M.D., is Director, FDA Oncology Center of Excellence

FDA Announces Two Initiatives to Modernize Drug Quality Programs

By: Janet Woodcock, M.D., and Michael Kopcha, Ph.D., R.Ph.

Patients expect and deserve high-quality drugs – this means consistently safe and effective medicines, free of defects and contamination. To satisfy these important expectations, the FDA strives to make sure that FDA-approved drugs are manufactured to meet quality standards to ensure that every dose is safe, effective, and capable of providing its intended benefit.

Janet Woodcock

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

Quality metrics are used in a variety of industries to monitor the quality control systems and processes that ensure standards are met, and to identify opportunities for manufacturing improvements. For the pharmaceutical industry, the use of quality metrics offers potential benefits to patients, manufacturers, and the FDA – including the potential to better combat drug shortages.

With these benefits in mind, the FDA has announced two new voluntary programs – the Quality Metrics Feedback Program and the Quality Metrics Site Visit Program – in response to stakeholder requests for continued dialogue on quality metrics, and to provide methods for industry to engage and inform the FDA’s use of them in the future. The programs will also help drug manufacturers to gain a better understanding of how quality metrics are a common feature of quality culture, and support improvements in product and process quality.

Feedback from early adopters and manufacturers who implemented quality metrics programs to address manufacturing problems, as well as independent academic research supported by the FDA, indicates that a manufacturer’s overall quality program benefits from the use of quality metrics. Quality metrics, such as data on the rate at which manufactured lots have been rejected for failing to meet established standards, can help manufacturers monitor quality control systems and drive continuous improvement efforts. For the FDA, data on quality metrics can help us better assess risk when scheduling inspections. This has the potential of decreasing the frequency of surveillance inspections for lower-risk establishments and narrowing the focus of on-site inspections conducted.

Michael Kopcha

Michael Kopcha, Ph.D., R.Ph., Director of the Office of Pharmaceutical Quality, FDA’s Center for Drug Evaluation and Research

The proximal cause of many drug shortages are quality issues such as substandard manufacturing facilities or processes. Quality metrics can be useful in identifying situations in which a drug supply disruption may occur, which can help mitigate potential future drug shortages. This will help to reassure patients that quality medicines will be available when they need them.

  • The Quality Metrics Feedback Program solicits information from drug manufacturers and sponsors that have implemented and are currently using quality metrics programs. The FDA is encouraging applicants eligible for Type C meetings as well as abbreviated new drug application (ANDA) holders to submit meeting requests to the FDA to discuss quality metrics for specific products. As part of the feedback effort, the FDA is also beginning a pilot study to gain feedback from other types of establishments where these types of meetings are not applicable, such as active pharmaceutical ingredient suppliers, over-the-counter monograph product establishments, and contract manufacturing organizations (CMOs).
  • The purpose of the Quality Metrics Site Visit Program is to provide on-site, firsthand learning opportunities to the FDA staff involved in the development of the FDA Quality Metrics Program. The Site Visit Program also is intended to provide stakeholders with the opportunity to explain the advantages and challenges they’ve experienced when implementing and managing their quality metrics programs.

The FDA’s new initiatives continue to enhance the focus of the conversation between the FDA and drug manufacturers to better understand – and make use of – quality metrics programs. We are confident these efforts will improve both the efficiency and the effectiveness of drug manufacturing, helping to assure a reliable and high-quality drug supply.

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

Michael Kopcha, Ph.D., R.Ph., is Director of the Office of Pharmaceutical Quality, FDA’s Center for Drug Evaluation and Research

FDA Budget Matters: Investing in Advanced Domestic Manufacturing

By: Scott Gottlieb, M.D.

There’s new technology that can improve drug quality, address shortages of medicines, lower drug costs, and bring pharmaceutical manufacturing back to the United States. At the FDA, we’re focused on propelling these innovations, collectively referred to as advanced manufacturing.

Dr. Scott GottliebAdvanced manufacturing, which includes various technologies, such as continuous manufacturing and 3D printing, holds great promise for improving the American market for drugs and biologicals.

Consider continuous manufacturing. These methods integrate traditional step-wise manufacturing processes into a single system that’s based on modern process monitoring and controls. This enables a steady output of finished drug products even as raw materials are continuously added to the closed system. The closed and continuous nature of these manufacturing systems means that the process is easier to control. These systems also require smaller footprints to operate.

And they’re far more efficient than standard manufacturing processes.

3D printing is another approach to advanced manufacturing. These methods are capable of manufacturing pre-determined 3D geometric structures of solid drug products in various shapes, strengths and distributions of active and inactive ingredients. This approach provides a unique opportunity to produce medicines that are tailored for individual needs of patients.

But harnessing the potential of these innovations requires deliberate private and public investments and new policy development. We need to define how these new technologies will be regulated for their reliability and safety. And provide clear guidance on how they can be adopted by sponsors.

The FDA is taking many steps to help realize the potential of advanced manufacturing. We’ve been issuing guidance on emerging technologies and approving continuous manufacturing for several New Drug Applications. However, to drive an earnest and more efficient conversion to these often-superior platforms, it’s going to take a broader effort on the part of the Agency.

The bottom line is this: Drug makers won’t switch to these systems until we create a clear path toward their adoption, and provide more regulatory certainty that changing over to a new manufacturing system won’t be an obstacle to either new or generic drug approvals. The FDA recognizes that it’ll require additional investment in policies and programs that’ll provide regulatory clarity to enable these new methods to be more quickly and widely adopted. To achieve these goals, the President’s fiscal year 2019 budget dedicates $58 million to accelerate the development of the regulatory and scientific architecture needed to progress this technology.

diagrams of continuous and batch manufacturingMany of the technologies currently used in traditional “batch” drug manufacturing – where the ultimate finished product is made after many stops and starts in a series of steps – are decades old. This shouldn’t come as a complete surprise. Drug development is a risky endeavor. After drug makers have navigated the years of risk involved in discovering and developing a new medicine, the last thing they want to do is inject a whole bunch of uncertainty at the last step toward approval – the adoption of the manufacturing process. So most drug makers have continued to use tried and true methods, even if these conventional processes have shortcomings.

However, this customary calculus is changing.

These continuous manufacturing systems are more ideally suited to new trends in drug development, such as personalized medicine and regenerative medicine products. Drugs that target small patient populations will require much greater manufacturing flexibility. The small scale of continuous manufacturing equipment works well for these endeavors. Close and continuous manufacturing systems can provide cost-effective drug product for early stage clinical development and yet can easily ramp up production for commercialization.

While development trends and market forces have made the commercial impetus for private capital investment in these technologies clear, meaningful adoption will not occur without supporting regulatory science and a collaborative regulatory environment. To drive adoption, the FDA will need to establish clear principles for how these new platforms will be evaluated and approved. We need to invest in the regulatory science to develop policies to support these innovations. That includes, for example, the development of analytical tools for monitoring these continuous systems. While much of this scientific work will be done outside the agency (typically through public and private partnerships) the basic regulatory principles need to be defined by the FDA.

The FDA has recognized and embraced the potential for this technology for years. We established an Emerging Technology Team in 2014 that works collaboratively with companies for both new and currently marketed drugs to support the use of advanced manufacturing.

The FDA’s Center for Biologics Evaluation and Research is building on that effort. We’re advancing the application of continuous manufacturing and other cutting-edge technologies. These manufacturing approaches may be ideally suited to new biological platforms like cell and gene therapies, as well as vaccines. In some cases, these manufacturing approaches may be the key enabling technology for the safe and effective development of these new biological platforms.

Take gene therapy as one example. Many gene therapies are being developed for very small populations ranging from tens to hundreds of patients. It can be costly and slow to build traditional manufacturing platforms to support such small yields, or to switch from a small, research grade manufacturing platform to one capable of supporting bigger trials, or commercial launch. And when it comes to products like gene therapies, a lot of the uncertainty is in how these products are manufactured. So, switching between different manufacturing platforms can create risk.

Applying continuous manufacturing approaches to these products could allow for the development of a quality manufacturing process that could support the production of enough commercial grade product to conduct an initial clinical trial as small as 10 to 20 patients. This would represent one production “cassette.”  Using continuous manufacturing, the scaling of manufacturing for larger trials wouldn’t require the build out of a completely new manufacturing facility. It would just require the introduction of additional “cassettes” into the closed system. Subsequently, if the clinical trial produced definitive data on safety and efficacy, then marketing could commence with product produced by making use of additional manufacturing cassettes. This could have a transformational effect on the costs and feasibility of applying gene therapy to rare diseases.

These manufacturing technologies are not only suited to emerging technologies, but also help address old challenges, like issues with drug shortages and pharmaceutical quality.

Drug shortages are a serious public health issue. What’s not widely known is that quality issues cause the majority of drug shortages. These quality issues are often related to facility remediation efforts and product manufacturing issues. Drug shortages have consequences for patient access to critical and lifesaving drugs. They also can cause prices to rise, in some cases substantially.

Continuous manufacturing systems may be far less prone to the shortcomings that trigger many drug shortages. This technology also reduces the number of steps in the manufacturing process and centralizes all manufacturing steps in one location. Simplification and centralization, in turn, allows for issues to be identified – and remedied – more quickly. In this way, continuous manufacturing helps address the primary root causes of drug shortages. Advanced manufacturing techniques also allow for more flexible manufacturing capacity, which enables manufacturers to respond to drug shortages faster. With these systems, drug makers can more quickly adjust volumes based on product demand and therefore release product to the market more quickly.

This flexibility – and the capacity to increase production easily – could also be important for vaccines; both for seasonal flu and vaccines to combat new outbreaks.

For example, egg-based vaccine manufacturing requires about six months to meet demand, which requires the World Health Organization and public health agencies to predict the flu strand six months prior to the flu season. In contrast, advanced manufacturing has the potential to expedite the process, shortening the amount of time between when the flu strain is selected and distributed.

This can allow us to produce the vaccine closer to the flu season, when we might have more certainty about the circulating strain. It also allows us to switch the strain more easily in the event of an unforeseen change. Or to produce a new vaccine in the event of a pandemic. These approaches also enable easier scaling of manufacturing if vaccine supplies should run short.

This additional flexibility when it comes to manufacturing can also provide a critical boost for emergency preparedness products, enabling manufacturing that can be more easily scaled to quickly respond to new threats. Consider when access to a vaccine is a key strategic need; for example, a vaccine to guard against a bioterror threat. Instead of stockpiling massive volumes of the vaccine; we would instead be able to mothball a just-in-time continuous manufacturing platform. The system could then scale up production in the event of an infectious threat.

Advanced manufacturing also provides an opportunity for the U.S. to regain a leadership position in pharmaceutical manufacturing and bring more high-quality manufacturing jobs back to this country. Many of the products that would benefit from advanced manufacturing are breakthrough-designated drug products that are usually first approved and marketed in the U.S. But many are still manufactured overseas. The traditional approach to manufacturing drugs requires large facilities and a lot of manual labor. Drug makers have made a calculation that these manufacturing sites can be operated more cheaply in countries with lower labor costs.

Continuous manufacturing changes this calculus.

These advanced platforms are small footprint operations. They require a reduced complement of more highly skilled workers. It’s the sort of manufacturing where America excels.

The U.S. is the current pioneer for advanced manufacturing. Our investments in educating engineers and establishing a research base for the development of domestic facilities will ensure that we maintain our lead in the world. Many U.S. universities have already established advanced manufacturing academic programs that train on these approaches. Some are funded through grants from the FDA that were authorized in 21st Century Cures. These approaches have also been applied with success to other fields, such electronic devices and chemical industries.

Producing more drugs domestically doesn’t just mean more American jobs. It could also reduce import costs for manufacturers and increase security of our supply chain.

Continuous manufacturing technologies could save 30 percent in manufacturing costs. This estimate does not include the savings from potential future technologies. That totals $60 billion per year in savings in the United States. This can help reduce drug costs. PCAST estimates that “Continuous manufacturing may reduce manufacturing costs, which currently consume as much as 27 percent of the revenue for many pharmaceutical companies, by up to 40 to 50 percent.”

One example of promising investment in these technologies is recent efforts by General Electric to “launch prefabricated manufacturing units for producing virus-based gene and cell therapies, novel anti-cancer treatments and vaccines.” Innovations like these could make it more feasible for small, innovative biotech companies to enter the market and compete against larger pharmaceutical companies, especially for gene and cell-based cancers. This could provide a broader array of innovation, and infuse more competition into these promising therapeutic areas.

The agility of continuous manufacturing platforms should ultimately reduce costs of drug manufacturing and could provide savings to our health system. But the efficient adoption of these approaches will require a paradigm change in the regulation of manufacturing. And that will require an investment to write new principles for how the FDA oversees these tasks. This is the opportunity before the FDA, and the heart of the proposal in the President’s budget.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Additional Resources:

“Continuous Manufacturing” -Common Guiding Principles Can Help Ensure Progress

Establishment of a Public Docket-Submission of Proposed Recommendations for Industry on Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing

Spotlight on CDER Science: Modernizing the Way Drugs Are Made: A Transition to Continuous Manufacturing

Emerging Technology Program

FDA Budget Matters: A Cross-Cutting Data Enterprise for Real World Evidence

By: Scott Gottlieb, M.D.

Over time, as our experience with new medical products expands, our knowledge about how best to maximize their benefits and minimize any potential risks, sharpens with each data point we gather. Every clinical use of a product produces data that can help better inform us about its safety and efficacy.

Dr. Scott GottliebThe FDA is committed to developing new tools to help us access and use data collected from all sources. This includes ways to expand our methodological repertoire to build on our understanding of medical products throughout their lifecycle, in the post market. We don’t limit our knowledge to pre-market information, traditional de novo post-market studies, and passive reporting. Newer methodologies enable us to collect data from routine medical care and develop valid scientific evidence that’s appropriate for regulatory decision making to help patients and health care providers prevent, diagnose, or treat diseases.

This includes our ability to leverage what’s often referred to as “real world data.” Real world data consists of data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources, including information obtained at the point of care. By using this information, we can gain a deeper understanding of a medical product’s safety and benefits, its additional treatment implications, and its potential limitations. By better leveraging this information, we can also enable more efficient medical product development by integrating greater complements of safety and benefit information gleaned from clinical care. This is especially true when it comes to our important obligation to continue to evaluate products in the post-market setting.

Traditional randomized clinical trials can provide key information on a medical product’s performance to support regulatory marketing decisions and health care decisions made by patients and providers. However, traditional clinical trials have their own limitations. The FDA, along with others, sometimes benefit from more information than these trials can provide about how medical products are used in medical practice.

For example, traditional clinical trials have patient inclusion and exclusion criteria that often narrow the patient population that can participate in a traditional trial. So, patients who’ve undergone another treatment, or who are taking other medications, may not qualify for a certain trial that’s looking for patients who haven’t been treated for that disease or condition, or who are taking certain medications.

When this product comes to market, it’s possible that patients who pursued other treatments or patients taking medications for other conditions will be prescribed this therapy. Because these patients weren’t studied, there’ll be no clinical trial evidence available showing how these other factors may affect the safety or efficacy of this product. Clinical trials provide a picture of a medical product’s potential in a narrow and highly controlled setting. But they do not provide a complete picture as to how a product works outside of that setting. This can limit our broader understanding of how a new product will work in “the real world.”

Real World Evidence diagramThe FDA is uniquely positioned and qualified to lead the effort to expand the use of real world data to address these knowledge gaps. Over the past decade, through the FDA’s Sentinel System and the National Evaluation System for health Technology (NEST), the FDA has begun to harness formerly untapped information to help us answer some of the most pressing questions facing patients and providers about the use of medical products. This use of real world data is referred to as “real world evidence.” This is meant to express the use of real world data to generate practical clinical evidence regarding the potential benefits or risks of a product. In this case, the evidence is derived from analysis of real world data.

We’re working to promote and expand the use of both real world data and real world evidence in medical product development and regulatory science. And not only for FDA uses, but also for others that seek to answer critical questions about health care delivery. To accomplish this goal, the FDA will leverage our knowledge and skills from building and using the Sentinel System and further supporting the development of NEST. Most importantly, we must develop the means to govern the responsible use of these data and to provide timely access to a broad group of public and private entities through the creation of a national resource. All the while, we must maintain strict data security and privacy of personal information.

To these ends, as part of the President’s Fiscal Year 2019 Budget, we’ve put forward a $100M medical data enterprise proposal to build a modern system that would rely on the electronic health records from about 10 million lives. This system would expand the data enterprise that we already maintain by incorporating new information from electronic health records, and other sources that would allow us to more fully evaluate medical products in the post-market setting.

This is the next evolution in the Agency’s development of a comprehensive data enterprise to improve medical product regulation and better inform us on the safety and benefits of new innovations.

Post-Market Data Sources: Claims Data vs. EHRs

Previously, our investments in post-market data have mostly focused on the development of systems to consolidate and analyze information derived from healthcare payer claims. This was a key advance in our regulatory system. And relying on health claims information was the state of the art at the time that we built these systems. Now we have the capacity to use clinical data derived from electronic health records to develop faster reporting on the performance of medical products in real world medical settings.

Claims data provides important insights. But it also has some limitations. For example, there’s an inherent lag between when a medical event occurs, and when it’ll show up in payer claims. There’s also some ambiguity in this process. It’s not always clear, by looking at claims data alone, what actually happened to the patient and whether the medical product was a factor. So, in the current system, we need to make certain assumptions when we evaluate claims data, to draw conclusions from this information. And some of these assumptions can inject uncertainty. The FY 2019 Budget request seeks to address some of these limitations by giving the Agency the ability to access the clinical medical information contained in de-identified electronic health records.

Investments in such a system can become a national utility for improving medical care, and allowing the FDA to optimize its regulatory decisions. It would give patients and providers the access to near-real-time, post-market information that can better inform their decisions. Such an enterprise can not only support our evaluation of safety and benefit using data derived from real-world settings, but it can also make the development of new innovations more efficient. If we have more dependable, near-real-time tools for evaluating products in real-world settings, we can allow key questions to be further evaluated in the post-market setting. This can allow some of the cost of development to be shifted into the post-market, where we can sometimes access better information about how products perform in real-world settings.

Establishing a System that can Leverage All Data Sources

Real world data can come from many sources. It not only can include electronic health records, but also claims and billing activities, product and disease registries, patient-related activities in out-patient or in-home use settings, and mobile health devices. It’s key that the sources of these data elements, such as different health care systems, be able to communicate electronically. This requires full “interoperability” and the elimination of any silos. The FY 2019 Budget request seeks to establish these building blocks, and assemble the data into an interoperable platform. There are several foundational steps that we’re already undertaking to build a strong programmatic basis for using real world data and evidence.

Achieving interoperability and establishing data standards, while conceptually obvious, is by no means easy to accomplish. Different groups may collect the same information in different ways. Consider that one group collects temperature using Celsius and another uses Fahrenheit. The group that uses Celsius may document a temperature of 37 degrees, while the one that uses Fahrenheit would document a temperature of 98.6 degrees. While these both are the same finding, in the absence of data standards, they would appear drastically different. Therefore, one key to this effort is the development of data standards and agreed upon definitions that allow different groups to meaningfully share their data.

Additionally, as noted above, there are many potential sources of real world data. Our familiarity and ability to harness these data varies across these sources. For example, the Sentinel System has taken advantage of a well-established source of real world data, claims and billing data. But claims and billing data, while well established and characterized, don’t necessarily capture the full scope of actual patient treatment. When it comes to medical devices, these claims data may not include the Unique Device Identifier which can limit the utility of the information. In addition, physicians may not be recoding every treatment in claims and billing data because of payment bundles, so the exact treatment is not known.

In comparison, electronic health records capture more of the patient experience and have the potential to provide more “real-time” information. But the information is also captured in a much less standardized way. Often key information is documented in unstructured ‘free text’ as part of a provider’s note. So, standardizing this information — and assembling it into formats that can allow for easier analysis and integration — will take additional investment in systems that can consolidate this information and make it interoperable.

Part of our proposed investment will go toward building these new capabilities to assemble real world data into formats to make this information more accessible. Ultimately, our goal is that such a tool can become a national utility that can be accessed by qualified research partners to inform a host of important clinical questions.

Improving Clinical Trials

The development of such a tool can also make the entire clinical trial process much more efficient. And it can enable us to enroll more patients from more diverse backgrounds into trials.

For example, real world data can be used to more efficiently identify and recruit patients for a clinical trial. Key design considerations, such as randomization, can be integrated across clinical care settings, introducing a much more diverse population into the clinical trial system. Innovative statistical approaches — such as Bayesian and propensity scores methods — can combine information from different sources and potentially reduce the size and duration of a clinical trial while expanding the scope of healthcare questions that we’re able to evaluate. This will enable a modern clinical trial system that improves upon trials being conducted in large medical care centers. It could enable more clinical trials at smaller community-based health care providers. Such a system can expand the number of patients we’re able to evaluate, and broaden the information that we’re able to collect, while at the same time reducing the cost of developing this information. We can have more and better information, and a less costly process.

All of this is contingent upon our ability to have confidence in the quality of data we’re accessing to make decisions, be that regulatory or derived from individual patient care.  We’re working with public and private partners to ensure optimal data quality, validity, and utilization. Our goal is to develop better data standards, to promote interoperability, and improve data quality.

Investing in Tools to More Wisely Use Data to Improve Health

Data quality has different impacts when considering the use of this data for individual patient care as opposed to broader public health evaluations. However, our capacity to make effective use of real world data and real world evidence will have a profound impact on individual patients and the public health.

Investing in the creation of a national resource that leverages real world data, establishes data standards to facilitate interoperability, and promotes data quality for the integration of this evidence into medical product development and clinical care is a key national investment. It’ll improve patient care, and make the process for developing safe and effective new medical innovations more efficient. It’ll give us a near real-time tool for monitoring the post-market safety of medical products, and will help inform better and more timely regulatory decisions.

Most importantly, such a system will provide patients with better care and more informed treatment decisions. The wider use of real world data could decrease the cost of product development, while increasing our understanding of how, when, and in whom, to use medical products. It’ll allow us to use the post-market period to refine our understanding of medical products. And it’ll allow us to make reliable post-market information available to providers and patients to better inform their treatment decisions.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

The American Chamber of Horrors

By: Vanessa Burrows, Ph.D., Suzanne Junod, Ph.D., and John Swann, Ph.D.

In the early 20th century, Americans were inundated with ineffective and dangerous drugs, as well as adulterated and deceptively packaged foods.

A cosmetic eyelash and eyebrow dye called Lash Lure, for example, which promised women that it would help them “radiate personality,” in fact contained a poison that caused ulceration of the corneas and degeneration of the eyeballs. An elixir called Banbar claimed to cure diabetes as an alternative to insulin, but actually provided no real treatment and caused harm to those patients who substituted this for effective insulin therapy. Food producers short-changed consumers by substituting cheaper ingredients. Some products labeled as peanut butter, for instance, were filled with lard and contained just a trace of peanuts, and some products marketed as “jellies” had no fruit in them at all.  Unscrupulous vendors even sold products to farmers, falsely promising they could treat sick animals – in at least one case, a product called Lee’s Gizzard Capsules killed an entire flock of turkeys instead of curing them.

Although the FDA sought to remove these unsafe and misleading products from commerce, it was severely limited in its efforts by the 1906 Pure Food and Drugs Act.  That law laid the cornerstone for the modern FDA and marked a monumental shift in the use of government powers to enhance consumer protection by requiring that foods and drugs bear truthful labeling statements and meet certain standards for purity and strength.

Over time, however, the shortcomings of the Pure Food and Drugs Act became apparent, as it failed to take into account the extraordinary changes in industries, products, markets, and advertising tactics. Dangerous drugs were a particular problem. As long as a drug met the law’s labeling requirements, the agency did not have the authority to remove even clearly dangerous products such as radium water and drugs with poisonous ingredients from the market because legal action against a drug product required a finding of fraud. If a drug’s maker could convince a court that he truly believed his own therapeutic claims, he won his case. In addition, the law provided no authority over cosmetics or medical devices, and did not specifically authorize standards for foods, which limited the agency’s ability to take action on behalf of consumers.

A popular book of the day, “100,000,000 Guinea Pigs: Dangers in Everyday Food, Drugs, and Cosmetics,” claimed that consumers were being used as guinea pigs in a giant experiment by food companies and makers of patent medicines, with the authors blaming the FDA for failing to act. But the critics failed to acknowledge the limits of the agency’s authority under the law at the time.

In an effort to inform the public about the 1906 law’s shortcomings, the FDA’s Chief Education Officer, Ruth deForest Lamb, and its Chief Inspector, George Larrick, led the creation of an influential traveling exhibit in 1933 to highlight about 100 dangerous, deceptive, or worthless products that the FDA lacked authority to remove from the market.

The exhibition was put on display at events like the 1933 World’s Fair in Chicago, at state fairs, and on Capitol Hill. It was so shocking that it was dubbed the “American Chamber of Horrors” by a reporter who accompanied First Lady Eleanor Roosevelt to view the exhibit. Lamb also adapted the exhibit into a 1936 book in which she explained, “All of these tragedies…have happened, not because Government officials are incompetent or callous, but because they have no real power to prevent them.”

The exhibit, which was viewed by millions, was an enormous success, helping promote greater awareness and understanding about the FDA’s role in protecting the public and the need for greater consumer protection and the limitations on its power to do so. To this end, it played an important role in moving Congress to enact a stronger food and drug law – the 1938 Food, Drug, and Cosmetic Act.

The 1938 law, which has been amended many times and remains the law of the land today, brought cosmetics and medical devices under the FDA’s authority, and required that drugs be labeled with adequate directions for safe use. It also mandated pre-market approval of all new drugs, such that a manufacturer would have to prove to the FDA that a drug was safe before it could be sold. And it prohibited false therapeutic claims for drugs. The Act also corrected abuses in food packaging and quality, and it mandated legally enforceable food standards. It formally authorized factory inspections, and added injunctions to the agency’s enforcement tools. In short, it gave the FDA many of the means it has today to protect the American public.

Many of the products from the original Chamber of Horrors exhibit are in the FDA’s permanent collection, and, to commemorate the 80th anniversary of the 1938 law, they are part of a special display currently on exhibit at the FDA. The objects provide a compelling visual record of how far science has brought us from the worthless and dangerous elixirs, foods, and other consumer products of the early 20th century, as well as underscoring the essential role the FDA today plays in protecting and promoting American health.

Vanessa Burrows, Ph.D., Suzanne Junod, Ph.D., and John Swann, Ph.D., are FDA Historians

FDA Budget Matters: Infrastructure to Support Robust Generic Drug Competition

By: Scott Gottlieb, M.D.

The FDA launched its Drug Competition Action Plan more than a year ago, with the aim of advancing policies that would promote robust generic drug entry as a way to foster competition and lower drug prices. Access to drugs is a matter of public health. And among the best ways to help consumers get broader access to medicines is through policies that help ensure branded drugs are subject to timely generic competition.

Dr. Scott GottliebOur work is far from finished. But the policies we’ve advanced are already showing benefits toward these goals. The benefits we’ve seen reinforce the fact that policy can be used as a vehicle to advance these purposes.

New resources have also helped advance our work. Owing in large measure to the FDA’s implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA), which funded critical enhancements to FDA’s generic drugs program, our staff eliminated the backlog of generic drug applications. In 2017, we also approved the largest number of generic drugs in the FDA’s history.

As part of GDUFA, as well as through our own new efforts, the FDA also has put policies in place to promote generic drug development in areas where there’s inadequate competition. This includes a focus on developing new guidance aimed at promoting development of generic versions of complex drugs. These are drugs that are often harder to copy. By advancing clear, objective, science-based guidance for developing generic copies of complex drugs, we hope to foster more competition.

And the FDA also has improved the efficiency and predictability of the generic drug review process to help promote more robust generic drug competition. For example, we’re prioritizing the review of generic drug applications for which there are no blocking patents or exclusivities. The aim is to promote competition so that there are at least four approved applications for each product (including the brand drug). Our data shows that there are significant price decreases once there are at least three generic drugs on the market. Our new policy will help ensure that there is robust competition across the market that will drive down drug costs to consumers.

In addition, we’re taking other new steps to curtail various forms of “gaming” by brand companies, where some sponsors sometimes adopt tactics that seek to delay entry of generic competition.

But we know that we need to do even more to promote access and competition. And so we’ve put forward a broader plan, as part of the President’s Budget, to achieve these aims.

Toward these goals, the President’s fiscal year 2019 Budget Request included $37.6 million to fund two initiatives that will help modernize aspects of our generic drug review process.

The first initiative will create a new review platform — the Knowledge-aided Assessment & Structured Application (KASA) platform — to modernize generic drug review from a text-based to a data-based assessment. The KASA will enable a structured review that will make the application review process more efficient, and allow deficiencies to be spotted earlier. This will allow the FDA to provide earlier feedback to generic drug makers that will, in turn, help to reduce multiple cycles of application review, one of our key aims and a primary focus of our overall efforts to speed market access to new generic medicines. Going through multiple review cycles is one of the primary reasons why the approval of generic drug applications is sometimes delayed many years. The new KASA system will help sponsors submit high-quality and more complete applications on the first submission. It will decrease the risk that applications will be refused for receipt and reduce the number of review cycles that applications undergo.

We anticipate that the new platform will allow more generic applications to be approved after the first cycle. This will promote timely generic entry and increase overall competition.

The new platform will also enable more efficient and robust knowledge management across different aspects of the FDA’s review process, helping reviewers capture and manage all of the information about products allowing for more seamless and effective product surveillance based upon quality and risk. This system will benefit both the agency and generic drug sponsors by increasing overall speed and efficiency of the pre- and post-market processes.

Having a structured template that completely replaces the current largely narrative-based review will allow for more consistent and predictable entry and analysis of data. Current assessments require manual review of the entire application. KASA will enable automated analysis of some portions of the application, which will save time, and ensure consistency.

The second initiative is aimed at promoting the more widespread use of existing generic drugs by looking for ways to keep generic drug labeling up-to-date with the latest information about each medicine’s risks and benefits. Generic drugs are generally required to have the same labeling as the brand drug they reference. And the burden to update the labeling with new safety and effectiveness information is typically born by the brand company.

However, when brand reference drug companies voluntarily withdraw their marketing applications, they also stop updating their labeling. When this happens, the FDA loses a key mechanism that the agency relies on as a way to update generic labeling. This can stymie the ability to modernize generic labels. In turn, when labels become out-of-date, providers may not have complete information about the full range of benefits and risks of the product. This can serve to diminish the use of these lower cost alternatives.

Consistent with our current authorities, which allow for certain types of labeling changes to continue to be made for generic drugs after the brand drug is withdrawn, this budget request will provide the funding to allow the FDA to assume more responsibility to help bring these drug labels up to date. We intend to launch this initiative initially for oncology products.

Our goal is to help ensure that doctors and patients have up-to-date information for these products. This will better inform clinical decisions regarding these medicines, and help promote more widespread use of low-cost, generic alternatives. By ensuring generic product labels are up to date, we’ll promote wider and more clinically optimal use of these drugs, which can save patients money.

We appreciate that the appropriations committees of both chambers of Congress supported this budget request in their appropriations bills. Congress has long recognized the need for — and importance of – investments in our generic drug program and efforts to promote generic drug use. The benefits of these initiatives are significant to the FDA’s modernization and efficiency. They’ll help advance a robust generic drug market that drives product competition and lowers drug prices.

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

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Report Spotlights Achievements of FDA-Mexico Produce Safety Partnership

En Español

By: Stephen M. Ostroff, M.D.

The United States and Mexico are major trading partners in fresh produce. Each year, billions of dollars of fruits and vegetables move across the border. These include Mexican tomatoes, avocados, chilies, berries, cucumbers, lemons, and limes that reach U.S. consumers, as well as American apples, pears, grapes, onions, strawberries, potatoes, peaches and other produce that are sent to Mexico.

Stephen Ostroff, M.D.Both our countries benefit when we can help to ensure that these valuable commodities are safe for consumers on both sides of our borders. For that reason, the FDA-Mexico Produce Safety Partnership (PSP) was formed in July 2014, forging a stronger relationship between the FDA and Mexico’s National Agro-Alimentary Health, Safety, and Quality Service (SENASICA) and its Federal Commission for the Protection from Sanitary Risk (COFEPRIS).

We are pleased to share that our partnership is making real progress toward our goal of reducing the risk of foodborne illness associated with our produce trade. A new report, titled U.S. FDA-Mexico Produce Safety Partnership: A Dynamic Partnership in Action, provides some specific examples of this progress.

For example, the partnership recently worked to address the contamination of papayas grown in Mexico. In the fall of 2017, the FDA, SENASICA and COFEPRIS worked together to respond to four outbreaks of salmonellosis tied to Mexican-grown papayas. The Mexican agencies conducted inspections and sampled various farms and packing houses in several Mexican states, and shared their findings with the FDA. We were able to leverage their work and resources, along with the findings of our own outbreak investigation, to place four farms on import alert, thus providing information to the FDA inspectors who detained those products without having to physically examine them. SENASICA likewise implemented a regulatory response. In October 2017, Mexico strengthened its food safety oversight of papayas, which are subject to the Produce Safety Rule under the FDA Food Safety Modernization Act if they will be imported or offered for import in the U.S.

Chart - Mexico Exports of Fresh Produce to USAIn another example, in 2015, Listeria monocytogenes was detected in kiwi and apples grown in the U.S. and exported to Mexico. The exchange of information under the PSP, including the sharing of bacterial isolates and testing by both FDA and SENASICA laboratories, helped prevent more contaminated produce from entering Mexico. It also established a protocol for the future exchange of bacterial strains to improve detection and understanding of contamination.

These are just two of several instances in which the partnership has led to coordinated preventive activities in addition to enforcement activities that help to reduce the risk of foodborne illnesses and enable both countries to respond more rapidly to a potential or actual outbreak, better protecting both American and Mexican consumers.

Chart - U.S. Exports of Fresh Produce to MexicoBut the partnership has also provided benefits beyond individual outbreaks. Both countries have also been working collaboratively through working groups on institutionalizing approaches that reinforce preventive practices and rapid response to outbreaks. The groups have focused on information sharing, education and outreach, training, laboratory methods and processes, and how to respond effectively to outbreaks.

Looking to the future, the report outlines our five-year plan to increase engagement and the exchange of knowledge with key public and private partners. Through the partnership, we plan to also work on identifying common approaches for auditors and inspectors to better execute compliance and enforcement activities, and will create a strategy to conduct joint inspections and sampling. This will help both countries maximize their resources for the benefit of consumers on both sides of the border.

This is a long-term partnership. While there are differences in our systems, technologies, and environments, the U.S. and Mexico both want consumers to be confident in the safety of their food. By working together, we can achieve that goal.

Stephen M. Ostroff, M.D., is FDA’s Deputy Commissioner for Foods and Veterinary Medicine.