21st Century Cures Act: Making Progress on Shared Goals for Patients

By: Robert M. Califf, M.D.

Today, President Obama signed into law the 21st Century Cures Act, which, I am pleased to report, builds on FDA’s ongoing efforts to advance medical product innovation and ensure that patients get access to treatments as quickly as possible, with continued assurance from high quality evidence that they are safe and effective.

Robert CaliffCures will greatly improve FDA’s ability to hire and retain scientific experts. One of our ongoing challenges has been recruiting and retaining the experts we need in specialized areas to allow us to get our work done and meet our growing responsibilities. This is an especially important need given the tremendous advances in biological sciences, engineering, information technology and data science. Preventive, diagnostic and therapeutic strategies will become more complex with much greater potential for benefit and in some cases greater risk if used without adequate evidence to exclude risks that exceed potential benefits.

This new law rightly recognizes that patients should play an essential role in the development of drugs and devices to diagnose and treat their disease, since patients are in a unique position to provide essential insights about what it is like to live with and fight their disease. That’s been our perspective as well, and it’s why FDA has continued to advance the science of patient input through our patient-focused drug development program and our partner with patients program for medical devices. As it is, Cures will enhance these ongoing efforts to better incorporate the patient’s voice into FDA’s decision-making.

Cures will also support our efforts to modernize and improve efficiency in clinical trial design. This has been an important FDA priority for decades, but exciting new approaches are now available, and we need to develop a common understanding of which designs should be used for which clinical issues. In cancer, for example, we’re already weighing the use of common control trials, which share a control arm, involve multiple different drugs for the same indication, and may even involve different companies. One of the benefits of using a common control arm is that the overall number of patients who need to be recruited and enrolled decreases, thereby optimizing clinical trial resources and potentially shortening the time it takes to get a new study off the ground

Even without the benefit of Cures, patients have been well-served by FDA’s program efficiencies, emphasis on early meetings, and use of expedited pathway programs to speed approval and delivery of new drugs and devices to patients. Rather than passively processing product applications, FDA works to advise companies and inventors from the earliest stages of the development process on the kinds of medical products needed, how to do the necessary research, and how to viably and effectively translate from concept to product. This not only means that important new products will be developed as efficiently as possible but also that medicines and devices with no chance of success are identified much earlier so that money isn’t wasted on futile development. These programs have been embraced by developers of medical products in this country, and they are making a real and positive difference.

In the United States, the FDA uses expedited programs (fast track, priority review, accelerated approval, and breakthrough therapy) for drugs and biologics more than comparable drug and biologic regulators in other countries use theirs and as a result FDA is the first to approve a majority of novel drugs compared to our foreign counterparts.

For devices, this past year was the first full year of operation for FDA’s expedited access pathway (EAP) program, which helps speed the development and availability of certain medical devices that demonstrate the potential to address unmet medical needs for life-threatening or irreversibly-debilitating diseases or conditions. So far, we have granted 24 devices access to this program. Cures builds on EAP by creating the breakthrough device pathway.

The law establishes other new programs as well. For instance, the Limited Population pathway will help streamline the development programs for certain antibacterials and antifungals intended to treat targeted groups of patients suffering from serious or life-threatening infections where unmet need exists due to lack of available therapies. Approvals of these antimicrobials are expected to rely on data primarily targeting these limited populations. The statement “Limited Population” will appear prominently next to the drug’s name in labeling, which will provide notice to healthcare providers that the drug is indicated for use in a limited and specific population of patients. The limited population statement, additional labeling statements describing the data, and FDA review of promotional materials, will help assure these drugs are used narrowly to treat these serious and life-threatening infections while additional evidence is generated to assess safety and effectiveness for broader use.

Cures also creates a new program for  the development of regenerative medicine products, an important and exciting new field that deserves this special focus. The program designates drugs as regenerative advanced therapies and takes appropriate actions to improve the efficiency of development and to enhance the exchange of information among FDA, researchers and developers. An especially important element of this program is the creation of a research network and a public-private partnership to assist developers in generating definitive evidence about whether their proposed therapies indeed provide clinical benefits that are hoped for.

Looking ahead, much still needs to be done to spur product development. There have yet to be successful therapies identified for certain diseases, such as Alzheimer’s disease, where underlying scientific knowledge is still lacking.  In addition, we are only at the early stage in building a national evidence generation system based on registries, claims data, and electronic health records that will be a rich source of post-market data and an avenue for conducting more efficient research. Last week we published a consensus of FDA leadership on the use of real world evidence in the New England Journal of Medicine, focusing on the misperception that randomized trials and real world data are incompatible.  In fact, the use of randomization within the context of clinical practice will constitute a major advance in evidence generation and we are actively encouraging proposals with this combination of randomized trials conducted in real world practice. Cures provides support for continued exploration of the use of real world evidence in the regulatory context.

The law also addresses drug firms providing healthcare economic information to payers and formulary committees. This complex area will require careful delineation of principles to guide information exchange to enable these entities to appropriately assess the value of drugs.

With Cures, great progress has been made towards our shared goal of advancing regulatory science so that we can continue to speed the discovery, development, and delivery of medical products to prevent and cure disease and improve health while sustaining the evidence framework that enables assurance to the public of the safety and effectiveness of medical products. We are excited about the major advances in NIH funding, and welcome the increasing focus on rigorous translational science and data sharing reflected in the bill. Furthermore the funding of opioid addiction treatment and mental health services is a major positive element for our country and consistent with tremendous needs that we recognize.

FDA now stands ready to work with Congress, our sister federal agencies and the medical products ecosystem to implement these important provisions as we continue to work on behalf of all Americans to protect and promote public health and promote innovation in this exciting time.

Robert M. Califf, M.D., is Commissioner of the U.S. Food and Drug Administration

FDA 2015: A Look Back (and Ahead) – Part 1: Medical Product Innovation

By: Stephen M. Ostroff, M.D.

As the year draws to a close, I want to reflect on FDA’s many accomplishments in these previous 12 months, the last nine of which it has been my pleasure to serve as Acting Commissioner. FDA has broad responsibilities – indeed, we are tasked with overseeing products that account for about 20 cents of the consumer dollar — so we work on a wide range of topics in any given year. In this and two additional blog posts over the coming days I’ll cover some of our key accomplishments in 2015. Each blog will examine a different area of FDA’s work. This first post will focus on medical product innovation – our role in making safe, effective and innovative products available to patients who need them.

Acting FDA Commissioner, Stephen Ostroff, M.D.Scientific advances and unprecedented innovation in the sectors we regulate make it an exciting time to work at and lead FDA. To protect and promote the public health our regulatory decision-making must be nimble and current, adapted to the forward march of science.

One measure of our success is revealed in a study released in September by FDA’s independent Science Board. Mission Possible: How FDA Can Move at the Speed of Science documents the Agency’s progress and transformation over the last eight years, dating from a time when FDA had been increasingly unable to meet its scientific responsibilities due to chronic underfunding, a loss of scientific expertise, and the need to implement new legislative mandates without the resources to do so. In stark contrast, today FDA’s regulatory science enterprise is much stronger, which better allows us to effectively fulfill our commitment to protect the public health. The report also provides recommendations for future investments in regulatory science to assure FDA keeps pace with emerging trends in science and technology.

Medical Product Approvals

For many years now, we’ve strived to modernize and streamline the regulatory process along the entire development, review, and product oversight continuum.

The success of these changes is shown by the large number and wide variety of medical products we’ve approved across our medical product centers. So far this year, we have approved more than 40 novel drugs, including four new treatments for patients with multiple myeloma, two new drugs for patients with heart failure, and another robust year of approvals of drugs for rare or “orphan” diseases. We’ve approved several important vaccines, including one for serogroup B meningococcal disease, the first seasonal influenza vaccine to contain an adjuvant (intended for people 65 years and older), and a new indication for anthrax vaccine to prevent disease following exposure to anthrax – the first vaccine to receive an approved indication based on the Animal Rule (which provides for testing certain products on animals alone). And we saw the approval of several innovative devices that will make a positive difference in the lives of patients, including a device that extends the survival time of patients with brain cancer, and a transcatheter pulmonary valve that can be placed in certain patients with congenital heart disease, without requiring open heart surgery.

Our success is also measured in our speed and efficiency of approvals. The U.S. continues to lead the world in approving novel drugs first. And we’ve seen important progress in our device review program. Our average time to reach decisions on PMAs has dropped 36 percent since 2009. And not since 2001 FDA has approved as many medical devices under the original premarket approval pathway and the panel track supplement pathway (for significant changes to a PMA device) as we did this year – 58 as of December 14th.

The number of approvals, and the agency’s ability to review products efficiently, continue to be buoyed by FDA’s expedited development and review programs. When we talk to drug and device makers at the early stages of development, and apply better regulatory science to our ultimate review of their applications, products that are likely to fail are weeded out, allowing manufacturers to focus on those more likely to attain approval.

Most importantly, enhanced flexibility and an efficient approval process have come without lowering our gold standard of safety and efficacy. At the end of the day, innovative therapies are only helpful to patients if they work and are demonstrated to be safe. So it is imperative that we ensure the right balances among patient access, sound science, and safe and effective products.

Amplifying the Patient Voice

Enhancing the patient’s voice in the medical product approval and evaluation process is an important emerging area of product development, which we have embraced in a number of ways.

Those living with a disease are in a unique position to provide essential insights about life with their condition, its severity, and the adequacy of treatment options. We also recognize patients and caregivers have their own perspectives on benefits and risks of medical products, and we believe this input should be considered during regulatory decision-making.

Our Patient-Focused Drug Development initiative is a five-year effort that includes holding at least 20 public meetings in different disease areas. Seventeen of those meetings have occurred and seven more are being scheduled. After receiving patient input during each meeting and in the agency docket, FDA develops a Voice of the Patient report that is then posted on our website. In a complementary effort, our medical device program launched the Patient Preference Initiative. It includes studies to evaluate patient preferences in medical devices, and publishing of a draft guidance that describes how patient tolerance for risk and perspective on benefit, in addition to clinical data and other information, may be considered in FDA’s benefit-risk assessments for certain medical devices. This year FDA approved a weight loss device treatment, and our decision was informed in part by data from a patient preference study funded and co-designed by the Agency.

In September 2015, FDA announced our first-ever Patient Engagement Advisory Committee, which will provide advice on complex issues related to the regulation of medical devices and their use by patients. This Advisory Committee will help ensure the needs, experiences, and perspectives of patients are considered in our work and incorporated in our decision-making.

Biosimilars

Five years ago Congress authorized an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product. The intent was to create greater competition in the medical marketplace that would not only increase treatment options for patients, but also lead to less expensive alternatives to comparable products. FDA has been developing its biosimilar program since then, an effort which led to the approval of the first biosimilar in March. And there are more applications in the pipeline. To prepare, FDA has produced a variety of guidances in this area, including the recent draft guidance on how these biosimilars should be named.

Advancing the Development of Next Generation Sequencing Tests and Strengthening Clinical Trials

Our strengthened focus on regulatory science is helping to drive innovation. One illuminating example is our growing ability to apply the sophisticated technologies of next generation sequencing and precision medicine.

FDA today is better prepared and more engaged than ever in facilitating the development of these new technologies (as well as new uses for older technologies), while assuring they are safe and effective. These efforts help to achieve more precise diagnosis or treatment, through the development and review of state of the art diagnostics that use genetic information to make therapies more targeted.

We continue to move forward on the White House’s Precision Medicine Initiative to advance biomedical understanding by leveraging genomic advances, health information technologies, and new methods of analyzing large volumes of data. Just this month, we launched FDA’s precisionFDA web platform, a cloud-based portal that will allow scientists from industry, academia, government and other partners to come together to foster innovation and develop the science behind next-generation sequencing and help us design treatments tailored to a person’s individual genetic blueprint.

And we also are working to refine clinical trial design and statistical methods of analysis to create more efficient studies with smaller patient populations, more focused therapies, and better outcomes. For instance, we continue to support collaborative efforts in clinical trials, such as the I-SPY trials (for breast cancer) and the Lung-MAP protocol (for lung cancer).

It’s impossible to capture in one blog post the many ways that FDA’s focus on regulatory science is helping drive innovation and speed the discovery, development, and delivery of medical products to prevent and cure disease and improve health. We are immeasurably proud of these accomplishments, which provide a strong foundation for continuing success.

Stephen M. Ostroff, M.D., is Acting Commissioner of Food and Drugs

FDA Advances Medical Product Innovation

By: Margaret A. Hamburg, M.D.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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