Two Recent Scientific Advances Underscore an Encouraging Future for Precision Medicine at FDA

By: Janet Woodcock, M.D.

FDA helps bring precision medicine – in the form of targeted therapies — to people living with diseases that have specific genetic features.

Two recent FDA drug approvals point to an encouraging future for “precision medicine” — an approach for disease treatment that tailors medical therapies, including medications, to the needs of individual patients. These approvals involve diseases resulting from particular genetic characteristics identified by laboratory testing.

  • In mid-May, FDA announced that we expanded the approval of Kalydeco (ivacaftor), enabling a larger number of patients with cystic fibrosis (CF) to benefit from the drug. The expanded approval includes CF patients with one of 23 additional rare mutations. Kalydeco is now indicated for 33 CF mutations, up from 10 previously.
  • Also in May, we announced expanded approval for Keytruda (pembrolizumab) to treat patients whose cancers have a specific genetic feature. This is the first time FDA has approved a cancer treatment based on a genetic feature, rather than the location in the body where the cancer originated.

Janet WoodcockFDA has approved many more advances in precision medicines, also called “targeted therapies.” In the past 3 years alone, our Center for Drug Evaluation and Research has approved more than 25 new drugs that benefit patients with specific genetic characteristics. And we have approved many more new uses — also based on specific genetic characteristics — for drugs already on the market. Some of these drug approvals are for patients with rare genetic disorders. Others are new targeted therapies to treat cancer, hepatitis C, or HIV. Medication dosing for specific diseases may also be tailored to the individual.

Precision medicine holds great promise, but to continue developing targeted therapies, we will need scientific advances in the use and development of “biomarkers.” Biomarkers are indicators in the body that can be measured—like blood pressure, blood sugar, and tumor size. Tests to identify genetic variants are another form of biomarker. Biomarkers can enable health care professionals and researchers to identify patients at risk of disease, determine the stage of a disease, and predict the likelihood that a patient will benefit from a drug. They also play a role in drug development. A particular biomarker, for example, can be used to identify appropriate candidates for a clinical trial, such as those patients likely to respond to treatment. This can make it easier and faster to recruit patients and may result in a shorter time for drug approval. In a similar way, biomarkers can sometimes identify positive treatment effects before traditional clinical endpoints would. For instance, biomarkers might show a tumor shrinking before improvement in a patient’s condition is detected. So, using biomarkers in clinical trials can speed up the time it takes for an investigative drug to reach a patient.

The ability to identify useful biomarkers depends on how well scientists understand the disease they are seeking to treat. In some areas, such as cancer and infectious diseases, we have made real progress in understanding how these diseases develop and how to treat them with drug therapy. FDA continues to encourage drug developers to use strategies based on biomarkers. One way we do that is by ensuring that a given biomarker is really able to single out those patients who are likely to respond to a specific drug. Another way is using biomarkers to identify people whose disease is progressing rapidly. Beyond working on biomarkers for individual products, FDA also works with stakeholders and scientific consortia in qualifying biomarkers that can be used in the development of many drugs. Once qualified, these biomarkers may be used in the specified manner by any drug sponsor.

New provisions under the recently passed 21st Century Cures Act provide direction and opportunity for FDA to strengthen the science of biomarkers and to advance precision medicine. We believe it is important to make drugs such as Kalydeco and Keytruda available to as many patients as can benefit from them. FDA is actively pursuing more advances in targeted therapies.

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

Continuous Manufacturing Has a Strong Impact on Drug Quality

By: Lawrence Yu, Ph.D.

If we used a time machine to transport a pharmaceutical scientist from the 1960s into a current pharmaceutical production plant of today, it might be surprising to learn that they would already be very familiar with most of the processes and production techniques being used. That’s because not much has changed in pharmaceutical production over the last 50 or so years.

Lawrence YuFor decades, most drugs have been manufactured using what is known as “batch” technology — a process whereby the ultimate finished product has been made after many stops and starts in a series of steps. Unfortunately each break in the process causes inefficiency and delay, as well as the increased possibility of defects and error.

Today, a new and exciting technology — continuous manufacturing — enables much faster production and more reliable products through an uninterrupted process. How much faster is continuous manufacturing?  In some cases, manufacturing that takes a month by batch technology might only take a day using continuous manufacturing techniques.

Of course, speed alone would not matter if continuous manufacturing compromised quality. But by eliminating breaks between steps and reducing opportunities for human errors during the stops and starts in the batch process, continuous manufacturing is more reliable — and safer. That’s a powerful combination.

There’s the added benefit that more efficient production of quality products can drive down manufacturing costs, possibly resulting in lower drug prices for consumers. Continuous manufacturing also allows manufacturers to respond much quicker to changes in demand, potentially contributing to prevention of drug shortages.

We are seeing a growing number of manufacturers working towards building continuous manufacturing into their processes. One manufacturer, Vertex, the maker of a cystic fibrosis drug called Orkambi (lumacaftor/ivacaftor) has been using the continuous manufacturing process for this drug since its approval date in July 2015.

Last Friday marked another significant step towards integrating continuous manufacturing into pharmaceutical production. FDA approved, for the first time, a manufacturer’s change in their production method from “batch” to continuous manufacturing. This new approval is for manufacturing Janssen Products, LP’s, medication for the treatment of HIV-1 infection, Prezista (darunavir). The company’s efforts in manufacturing advancement were facilitated by the use of FDA’s recently-released draft guidance to industry titled, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base, a product of the agency’s Emerging Technology Team (ETT) designed to help manufacturers implement a variety of technological advancements.

Although it is not easy for drug manufacturers to transition from batch to continuous manufacturing, there are significant rewards. FDA encourages others in the pharmaceutical industry to consider similar efforts.

Progress comes at an opportune time. The medications we use are changing. We are entering an era of precision medicine, when drugs must be made with unique features and provided more quickly to patients in need. FDA will continue our efforts to encourage the advancement of continuous manufacturing as one of a variety of ways to enhance the quality of the medications used by the American public.

Lawrence Yu, Ph.D., is FDA’s Deputy Director, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research

Priorities – Teamwork to Achieve Common Goals

By: Robert M. Califf, M.D.

With my appointment as Commissioner of Food and Drugs comes a rare and humbling opportunity—to make a positive difference at an institution that does vitally important work for the nation and its citizens. During my vetting process I received hundreds of emails and had almost as many conversations with a large and diverse group of stakeholders. Over the course of these discussions, a recurring theme emerged: namely, that setting priorities would be critical to success.

Robert M. Califf, M.D., Commissioner of the U.S. Food and Drug AdministrationThis is hardly surprising. FDA regulates about 20 percent of the nation’s economy and, given the vast number of options, it would be easy to get lost in an overwhelming swirl of activity. In fact, at times I have been (rightfully) accused of having an excessively lengthy to-do list! But my interactions with so many of the knowledgeable, dedicated, and mission-driven people here at FDA have helped foster a clear, realistic, and focused sense of priorities and have further heightened an already strong enthusiasm for helping this awesome organization reach these ambitious goals.

FDA makes decisions in a remarkably effective and responsible way. Guided by the lodestone of our mission to protect and promote the public health, and supported by the concerted efforts of dedicated and talented professionals who examine issues within team-based systems, FDA’s Centers that form the core of our organization are able to make an enormous number of decisions every day. The vast majority of these decisions, many of which are vital to the well-being of all Americans, are made possible by a system sustained by professionalism and a well-earned reputation for high-quality and impartial judgments—despite the fact that many decisions must ultimately disappoint (or at least not fully satisfy) one or more constituencies.

I strongly believe my most important responsibility during my time at FDA is to encourage and support a professional environment that enables our remarkably dedicated workforce to thrive and to reach its fullest potential. Dramatic advances in biotechnology and information sciences, as well as continuously accelerating trends toward globalization, are ushering in an era of rapid change. But amid this change, the key to success for the Agency in accomplishing its mission remains constant—sustaining and expanding our talented workforce and ensuring that we both hire the people we need for the future while we continue to enhance our environment to ensure that we retain existing staff. To that end, I will pursue a workforce initiative designed to 1) improve the hiring system, 2) ensure that the Agency has the best possible working conditions for staff, and 3) foster professional homes for the diverse professions that make up our teams so that we are able to recruit and retain them in a very competitive market.

My top programmatic priority will likely come as no surprise, given the astonishing changes that are currently rippling through society: we must do everything possible to rapidly adapt our national and global systems of evidence generation to meet the challenges and opportunities presented by technological advances. What does this mean? I’ve noticed that when high-quality evidence is available, FDA’s scientific decision making is often straightforward. But it can be particularly challenging for the Agency when it must make scientific decisions in the absence of optimal information. In such cases, opinions may carry greater weight, and there can be an increased likelihood of dissension both inside and outside of FDA, as well as a greater risk that we may fail to most fully protect or advance the welfare of patients and the public.

FDA is a science-based, science-led organization that focuses on the needs of patients and consumers; protecting their well-being is our charge as a public health agency. The state of the art as it pertains to understanding the needs and choices of patients and the public is progressing rapidly, and we must continue to keep pace by incorporating the best methods for taking patient preferences, experiences, and outcomes into account in every part of our work.

Biomedical science is nearing a tipping point where the amount of high-quality evidence available to support our decisions is likely to increase exponentially. As a nation, we have invested over $50 billion to provide an electronic health record (EHR) for almost every American. Further, computational storage capacity and analytical power are increasing by orders of magnitude from year to year. At the same time, the advent and wide diffusion of social media are enabling direct communication with patients and consumers on an unprecedented scale. When projects such as Sentinel and the National Medical Device Evaluation System are linked with the many complementary initiatives under way at our sister agencies and at organizations outside of the government, we can (and I believe in short order will!) build a robust foundation for a system in which both private and public sectors can produce much more useful knowledge at a fraction of the cost such efforts have previously required. Indeed, a major function of FDA is to support the continued development of an effective system for evidence generation, so that the private and academic sectors can make it happen.

Accordingly, FDA is thoroughly committed to working with the many partners in our ecosystem to help build and sustain an infrastructure that produces the high-quality scientific evidence needed to guide FDA’s decisions about the drugs, medical devices, tobacco products, and food products it’s charged with regulating, as well as the decisions that healthcare providers, patients, and consumers make about their health and well-being.

In addition to this overarching priority, a number of specific critical issues are on my front burner this morning and will remain there for the foreseeable future:

  • Pain. The present epidemic of opioid overdose deaths now exceeds deaths from automobile crashes. FDA cannot solve this problem on its own—and indeed, no single entity can—but we have a critical role to play, as described in our FDA Opioids Action Plan.
  • Tobacco product deeming. Much effort has gone into developing the framework for the approach to the regulation of the broad array of tobacco products. FDA is working hard to finalize the deeming rule, which in its proposed form would extend FDA regulation over virtually all tobacco products, including electronic cigarettes, either all cigars or all but premium cigars, pipe tobacco, certain dissolvables that are not “smokeless tobacco,” gels, and waterpipe tobacco.
  • Implementation of the FDA Food Safety Modernization Act (FSMA). This statutory directive to transform the food safety system is well on its way to being implemented, with critical regulations issued and more to come. The effort involves the complex development of a new control and risk-based system that includes the entire chain of food safety. Effective implementation of this system will require the application of cutting-edge analytical and biological science, as well as the most modern approaches to human systems management.
  • Antimicrobial resistance. Concerns about the proliferation of multidrug-resistant pathogens, as well as the sustainability of the product pipeline needed to meet this threat, continue to grow. We have a major responsibility in the federal plan, one that will involve many parts of the Agency and require that we work with the broad ecosystem, both to ensure that appropriate antimicrobials are used appropriately on farms, and that novel antimicrobials are developed, approved, and used responsibly within a framework of effective stewardship.
  • Interagency effectiveness. When we consider our mission to protect and advance the public health, as well as our duty to balance benefit and risk for patients and consumers of medical products, much of our success can be enhanced by coordinated effort across government. We have therefore continued the FDA-NIH Joint Leadership Council and the FDA-CDC meetings, and also initiated similar discussions with CMS. The Biomarkers, Endpoints and other Tools (BEST) Resource offers a powerful example of the ability of FDA and NIH to contribute to solving scientific and regulatory issues together.
  • Precision Medicine. President Obama’s Precision Medicine Initiative represents more than just a project. Rather, it is a window that provides a clear view of the future for biomedicine and agriculture, a future in which powerful new technologies and methods allow the precise targeting of interventions using an array of genetic, genomic, biological, clinical, social, and environmental data according to the scale needed to achieve improved health outcomes.
  • Cross-Cutting Issues. There are a great many other issues (truthfully, the number reaches triple digits) on my list of concerns. But those issues that cut across the Agency, including optimizing our approach to combination products, medical countermeasures, and improving product labeling, will benefit most from my attention and support.

A single introductory blog post is not suited for giving details about priorities or individual programs. However, I hope I’ve conveyed my enthusiasm for the work at hand, as well as my confidence that we will be able to make real and lasting improvements in many critical areas. I promise that we will follow up with frequent updates, as fostering effective communication is itself an overarching priority of immense importance to me. So expect to hear from me again soon!

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

FDA Continues to Lead in Precision Medicine

By: Janet Woodcock, M.D.

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

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

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

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

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

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

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

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

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

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

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

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