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 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

FDA Considering How to Tailor its Oversight for Next Generation Sequencing

By: Margaret A. Hamburg, M.D.

FDA is weighing the appropriate regulatory approach to advances in technology that allow physicians to obtain information on large segments of a patient’s genetic makeup very quickly.

Margaret Hamburg, M.D.This technology is known as next generation sequencing, where a single test potentially can be employed to identify thousands—even millions—of genetic variants carried by a single individual. The results of such tests could be used to diagnose or predict a person’s risk of developing many different conditions or diseases and potentially help physicians and patients determine what course of treatment should be used to treat specific individuals.

Reliable and accurate NGS technologies promise to accelerate “personalized” or “precision” medicine, the tailoring of medical treatment to the individual characteristics of each patient. But they also pose some novel issues for FDA in carrying out our mission of protecting and promoting public health.

Most diagnostic tests follow a one test—one disease paradigm that readily fits FDA’s current device review approaches for evaluating a test’s analytical and clinical performance. Next generation sequencing produces a massive amount of data that may be better handled using a new approach.

Last year we took steps to adapt our oversight approach to this new technology with the marketing authorization of the first NGS sequencing instrument, Illumina’s MiSeqDx Instrument and its two tests for cystic fibrosis (CF) mutations. We applied practical regulation to these products: we looked at how accurately the instrument sequenced a representative set of genetic variants across the genome rather than requiring data on every possible variant. Doing so avoided years of data gathering and unnecessary delay in the public’s access to the benefits of this technology while still assuring its accuracy and reliability.

Similar flexibility was employed in assessing the two CF tests. FDA allowed Illumina to leverage a well-curated, shared database of CF mutations to demonstrate the clinical value of its tests, rather than requiring them to independently generate data to support each mutation’s association with the disease.

In the future, next generation sequencing tests may be available to rapidly address new medical knowledge that can be applied in treating patients. Medical knowledge itself can be strengthened through creating databases of research and clinical information tied to particular genetic variants. FDA intends to develop a practical and nimble approach that will allow medical advances to be implemented as soon as possible, using its regulatory flexibility and the power of the information placed into high-quality databases.

This week President Obama unveiled his Precision Medicine Initiative. As part of that effort, FDA has been reviewing the current regulatory landscape involving next generation sequencing as the technology moves rapidly from research to clinical practice. To get the dialogue started, FDA published a preliminary discussion paper in late December that posed a series of questions about how to best assure that tests are not only accurate and reliable, but are available for patients as soon as possible. Public comment is essential, so FDA has opened a public docket and will be holding a public meeting on NGS technology on February 20.

NGS technology is clearly integral to the future of personalized medicine. Whatever approach FDA ultimately adopts must be selected with care to ensure continued innovation in the advancement of medical care and public health for this still evolving technology.

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

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

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

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

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

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

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

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

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

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

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

Developing new tools to support regulatory use of “Next Gen Sequencing” data

By: Carolyn A. Wilson, Ph.D.

When you’re thirsty, you don’t want to take a drink from a fire hose. And when scientists are looking for data they don’t want to be knocked over with a flood of information that overwhelms their ability to analyze and make sense of it.

Carolyn WilsonThat’s especially true of data generated by some types of both human and non-human genome research called Next Generation Sequencing (NGS). This technology produces sets of data that are so large and complex that they overwhelm the ability of most computer systems to store, search, and analyze it, or transfer it to other computer systems.

The human genome comprises about 3 billion building blocks called nucleic acids; much medical research involves analyzing this huge storehouse of data by a process called sequencing—determining the order in which the nucleic acids occur, either in the entire genome or a specific part of it. The goal is often to find changes in the sequence that might be mutations that cause specific disease. Such information could be the basis of diagnostic tests, new treatments, or ways to track the quality of certain products, such as vaccines made from viruses.

NGS is a complicated technique, but basically it involves cutting the genome into millions of small pieces so you can use sophisticated chemical tricks and technologies to ignore the “junk” you don’t need, and then make up to hundreds of copies of each of the pieces you want to study. This enables additional techniques to identify changes in the sequence of nucleic acids that might be mutations. NSG enables scientists to fast-track this process by analyzing millions of pieces of the genome at the same time. For comparison, the famous human genome sequencing and analysis program that took 13 years to complete and cost $3 billion could now be completed in days for a few thousand dollars.

Man with HIVE Computer

The Center for Biologics Evaluation and Research (CBER) supported the development of High-Performance Integrated Virtual Environment (HIVE) technology, a private, cloud-based environment that comprises both a storage library of data and a powerful computing capacity being used to support Next Generation Sequencing of genomes.

In order to prepare FDA to review and understand the interpretation and significance of data in regulatory submissions that include NGS, the Center for Biologics Evaluation and Research (CBER) supported the development of a powerful, data-hungry computer technology called High-Performance Integrated Virtual Environment (HIVE), which can consume, digest, analyze, manage, and share all this data. HIVE is a private cloud-based environment that comprises both a storage library of data and a powerful computing capacity. One specific algorithm (set of instructions for handling data) of HIVE that enables CBER scientists to manage the NGS fire hose is called HIVE-hexagon aligner. CBER scientists have used HIVE-hexagon in a variety of ways; for example, it helped scientists in the Office of Vaccines Research and Review study the genetic stability of influenza A viruses used to make vaccines. The scientists showed that this powerful tool might be very useful for determining if influenza viruses being grown for use in vaccines were accumulating mutations that could either reduce their effectiveness in preventing infections, or even worse, cause infections.

There’s another exciting potential to HIVE-hexagon research: the more scientists can learn about variations in genes that alter the way they work—or make them stop working–the more they can help doctors modify patient care to reflect those very personal differences. These differences can affect health, disease, and how individuals respond to treatments, such as chemotherapy and influenza vaccines. Such knowledge will contribute to advances in personalized medicine.

Team members at work in FDA's HIVE server room.

CBER scientists showed that HIVE might help scientists determine if influenza viruses being grown for use in vaccines were accumulating mutations that could either reduce their effectiveness in preventing infections or cause infections. Genome studies supported by HIVE will also contribute to advances in personalized medicine.

Because CBER’s HIVE installation has been so successful we are now collaborating with FDA’s Center for Devices and Radiological Health (CDRH) to provide a second installation with greater capacity and computer power that takes advantage of the high-performance computing capacity there. When ready and approved by FDA for use, we will use this powerful, CBER-managed, inter-center resource to handle regulatory submissions.

HIVE-hexagon and its innovative NGS algorithms are just one major step CBER has taken recently as it continues its pioneering work in regulatory research to ensure that products for consumers are safe and effective. I’ll tell you about other exciting breakthroughs in my next update on CBER research.

Carolyn A. Wilson, Ph.D., is Associate Director for Research at FDA’s Center for Biologics Evaluation and Research.

For more HIVE photos go to Flickr

FDA Innovation Brings New Therapies to Lung Cancer Patients

By: Richard Pazdur, M.D. and Gideon Blumenthal, M.D.

Last week, we approved a new drug for patients with a certain type of late stage, non-small cell lung cancer (NSCLC).

Richard Pazdur, M.D.

Richard Pazdur, M.D.

It’s one of four targeted therapies for lung cancer that have been approved since 2011—therapies that are the result of a new and forward-thinking approach to understanding the disease and its causes.

Within the last decade, the high quality of the data in the applications submitted to the agency and our collective understanding of the genetic and molecular underpinnings of lung cancer have enabled us to move from classifying the disease by what can be seen under a microscope, to looking at the patient’s molecular profile and classifying and treating the cancer by specific subtype. Scientists can now identify “driver oncogenes,” which cause a normal cell to become cancerous and promote the growth of a patient’s tumor. They can develop targeted therapies aimed at shutting down these aberrant genes and pathways, an example of an approach called personalized medicine.

Last week’s approval of Zykadia (certinib) provides a new treatment option for patients who comprise a relatively small subset of lung cancer and previously had few treatment options. While about 85 percent of lung cancers are NSCLC, making it the most common type, only about 5 percent of patients’ tumors are anaplastic lymphoma kinase (ALK) positive. Zykadia blocks this ALK protein that promotes the development of cancerous cells. In a clinical trial of 163 patients with metastatic ALK-positive NSCLC who had progressed on or were intolerant to a similar drug, results showed that tumors shrank in about half of the participants, and this effect lasted an average of seven months.

Gideon Blumenthal, M.D.

Gideon Blumenthal, M.D.

Moreover, the approval process exemplifies the important role of FDA and the strength of the collaborative process between FDA, industry, health advocacy organizations and other stakeholders. And it illustrates the dedication and enthusiasm of FDA reviewers who carefully, but expeditiously, analyzed complex study results to allow for earlier approval to support patient access to this new drug.

FDA granted breakthrough designation to this drug, thereby streamlining the development and review process with an “all hands on deck” approach. In fact, due to the enhanced understanding of ALK in lung cancer and the frequent interactions between the FDA and the commercial sponsor, it took less than four years—versus the roughly ten years it used to take—from the initial study of a drug to FDA approval.

We hope to further extend the collaborative effort in the future by participating in the use of the master protocol process. In a master protocol, multiple drugs and biomarkers can be tested in in a single, ongoing clinical trial. Under this approach, based on individual patient profiles, researchers can randomly assign patients either to one of several targeted treatments or to a control regimen of standard chemotherapy. We believe this will enhance the efficiency of clinical trials and help deliver safe and effective therapies to a patient population where few such therapies exist. Stay tuned: we hope to say more about this process in a future FDA Voice blog.

Of course, the progress we are making can’t come fast enough. There are far too many cancer mutations with few or no therapies developed thus far to treat them. But we and our colleagues throughout the medical research world are continuing to look for new and creative approaches to treat the disease. We’re well on our way.

Richard Pazdur, M.D. is Director of the Office of Hematology and Oncology Products at FDA.

Gideon Blumenthal, M.D. is the Team Leader of Thoracic Oncology in the Center for Drug Evaluation and Research at FDA. 

We Moved Forward on Many Fronts This Year

By: Margaret A. Hamburg, M.D.

At the FDA, the agency that I’ve had the privilege to lead for the past five years, I am gratified to report that we have a lot to be proud of this year. In fact, this past year’s accomplishments on behalf of public health have been as substantial as any in FDA’s recent history.

Margaret Hamburg, M.D.We moved significantly forward, for example, in creating a system that will reduce foodborne illness, approving novel medical products in cutting-edge areas of science, and continuing to develop our new tobacco control program. We worked successfully with Congress and with regulated industry to reach agreement on a number of difficult issues, while continuing to use the law to the full extent possible to protect consumers and advance public health.

While there were many significant actions and events to recognize, below are some of the highlights of 2013.

In the foods area, there were many new actions this year that will have a long-standing impact on improving our food supply for consumers. Throughout the year we have been proposing new rules to reach the goals set forth by the FDA Food Safety Modernization Act (FSMA). These science-based standards will help ensure the safety of all foods produced for our market, whether they come from the U.S. or from other countries.

We also took important steps towards reducing artery-clogging trans fat in processed foods, and understanding the health impact of arsenic in rice. With a final rule that defines when baked goods, pastas and other foods can be considered free of gluten, people with celiac disease can have confidence in foods labeled “gluten free.” And we are studying whether adding caffeine to foods may have an effect on the health of young people and others.

There have likewise been many accomplishments in advancing the safety and effectiveness of medical products. We worked closely with Congress on the recently enacted Drug Quality and Security Act, which contains important provisions relating to the oversight of human drug compounding. The law also has provisions to help secure the drug supply chain so that we can better help protect consumers from the dangers of counterfeit, stolen, contaminated, or otherwise harmful drugs.

Using tools provided by last year’s landmark Food and Drug Administration Safety and Innovation Act (FDASIA), we are continuing to improve the speed and efficiency of medical product reviews, including those involving low-cost, high quality generic drugs and innovative new medical devices. The average number of days it takes for pre-market review of a new medical device has been reduced by about one-third since 2010. The percentage of pre-market approval applications that we approve has increased since then, after steadily decreasing each year since 2004.

We launched a powerful new tool to accelerate the development and review of “breakthrough therapies,” allowing FDA to expedite development of a drug or biologic (such as a vaccine) if preliminary clinical evidence indicates that it may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. This offers real opportunities to get promising drugs more quickly to patients who need them. In fact, using this new approach, FDA recently approved two advanced treatments for rare types of cancer and one for hepatitis C. We have also strengthened efforts to ensure product quality, increased protection of the drug supply chain, and reduced drug shortages.

We confronted the growing misuse of powerful opioid pain relievers by advising manufacturers on how to make these drugs harder to abuse with formulations that are more difficult to crush for inhalation or dissolve for injection. And we recommended that hydrocodone combination products be subject to stricter controls to help prevent abuse. 

We took an important step towards fighting the development of antibiotic-resistant bacteria by implementing a voluntary plan to phase out the use of antibiotics to enhance the growth of food-producing animals, and to move any remaining therapeutic uses of these drugs under the oversight of a licensed veterinarian. So-called “production” use is considered a contributing factor in the development of bacteria that are resistant to the antibiotics used in human medical treatment.

In many areas of our work we are supporting the emerging field of personalized medicine. Advances in sequencing the human genome and greater understanding of the underlying mechanisms of disease, combined with increasingly powerful computers and other technologies, are making it possible to tailor medical treatments to the specific characteristics, needs, and preferences of individual patients.

Many cancer drugs today are increasingly used with companion diagnostic tests that can help determine whether a patient will respond to the drug based on the genetic characteristics of the patient’s tumor. In May, FDA approved two drugs and companion diagnostic testing for the treatment of certain melanoma patients with particular genetic mutations.

Advances in science and technology are also seen in the creation of new medical devices. For example, 3-D printing – the making of a three-dimensional solid object from a digital model – was once considered the wave of the future. But in February, FDA cleared for marketing a device created by 3-D printing – a plate used in a surgical repair of the skull that is built specifically for the individual patient.

While we have worked hard to get therapies to patients, we are at the same time using the tools available to us to remove unsafe and dangerous products from the market. In November, we used new enforcement tools provided by the food-safety law to act quickly in the face of a potential danger to public health presented by certain OxyElite Pro products. These supplements had been linked to dozens of cases of acute liver failure and hepatitis. After FDA took action, the manufacturer agreed to recall and destroy the supplements.

Finally, we made significant progress in implementing the letter and spirit of the Family Smoking Prevention and Tobacco Control Act. We have signed contracts with numerous state and local authorities to enforce the ban on the sale of tobacco to children and teens; conducted close to 240,000 inspections; and written more than 12,100 warning letters to retailers. And, in the first quarter of 2014 we will launch a public education campaign aimed at reducing the number of young people who use tobacco products.

All of us take great pride in the skill and vigor with which we overcame the year’s challenges and new demands. And so, as the year draws to a close, I extend my gratitude to the employees at the FDA who work tirelessly on behalf of the American public year in and year out. To all of our stakeholders, my heartfelt wishes for a joyous holiday season and a safe and healthy 2014.

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

Gene Sequencing Devices Are ‘Next Generation’

By: Jeffrey Shuren, M.D.

Just for a moment, imagine a scenario in which you have an illness that has eluded diagnosis. The usual suspects have been ruled out and no one knows exactly what’s making you sick. 

Using medical devices that FDA has now cleared for marketing, a laboratory could sequence your genome to look for any abnormalities in your genes that could be responsible for your illness. This information would be relayed to your doctor and used to determine the course of treatment.

This is called “next generation sequencing” because it’s another step towards a future in personalized medical care that few of us could have envisioned even a decade ago. 

First, let’s define some terms. A genome is the complete set of genetic information in your body. This information is held in sequences of DNA, and gene sequencing from your whole blood allows laboratories to look for genetic variations that could hold the key to the causes of disease and the right treatment. 

FDA is clearing the marketing of four gene-sequencing devices. Two of the devices make up the first test system authorized for marketing that allows laboratories to sequence a patient’s genome for any purpose. The software compares the patient’s sequence to a normal human genome sequence used for reference and identifies the differences. 

The other two devices are used to detect changes in the CFTR gene, which can result in cystic fibrosis, a disease inherited through a faulty CFTR gene from both parents. More than 10 million Americans are carriers of cystic fibrosis (they have only one faulty copy), and one of these tests could be used to identify men and women with the faulty CFTR gene. The second test looks for other, perhaps unexpected, mutations in the CFTR gene that could be having an impact on the patient’s health. 

Regulatory science – the science of developing new tools, standards and approaches to assess the safety, effectiveness, and quality of FDA-regulated products – played a key role in FDA’s readiness to assess these revolutionary devices. Knowing the potential of next generation sequencing to advance personalized medicine, FDA researched next generation sequencers to understand how they work and their likely limitations. By the time Illumina (the San Diego-based biotechnology company that developed the next generation sequencing devices authorized for marketing) walked in the door, FDA had the expertise and tools needed to timely review the submissions for the next generation sequencers. 

The regulatory science development efforts that contributed to the timely marketing authorization of these devices will continue to help advance this important technology. We are also collaborating with the National Institute of Standards and Technology – a federal agency that works to advance measurement science, standards and technology – and other agencies to develop human genome materials that can serve as reference materials so that other labs and researchers can assess the performance of their gene sequencers quickly, effectively, and at a lower cost.

We are working on many fronts to achieve the promise of personalized medicine, so that patients can get medical treatments that are right for them. Clearing the marketing of these four devices moves us closer to that goal.

For further perspective, read a new article in the New England Journal of Medicine by FDA Commissioner Margaret A. Hamburg, M.D. and National Institutes of Health Director Francis S. Collins, M.D., Ph.D.

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

Personalized Medicine: The Future is Now

By Margaret A. Hamburg, M.D.

Margaret Hamburg, M.D.The difference between science and science fiction is a line that seems ever harder to distinguish, thanks in part to a host of astonishing advances in medical science that are helping to create a new age of promise and possibility for patients.

Today cancer drugs are increasingly twinned with a diagnostic device that can determine whether a patient will respond to the drug based on their tumor’s genetic characteristics; medical imaging can be used to identify the best implantable device to treat a specific patient with clogged coronary arteries; and progress in regenerative medicine and stem cell therapy using a patient’s own cells could lead to the replacement or regeneration of their missing or damaged tissues. Given these trends, the future of medicine is rapidly approaching the promising level of care and cure once imagined by Hollywood in futuristic dramas like Star Trek.

But these examples are not science fiction. They are very real achievements that demonstrate the era of “personalized medicine” where advances in the science of drug development, the study of genes and their functions, the availability of increasingly powerful computers and other technologies, combined with our greater understanding of the complexity of disease, makes it possible to tailor treatments to the needs of an individual patient. We now know that patients with similar symptoms may have different diseases with different causes. Individual patients who may appear to have the same disease may respond differently (or not at all) to treatments of that disease.

FDA has been playing a critical role in the growth of this new era for a number of years. Even before I became FDA Commissioner the agency was creating the organizational infrastructure and putting in place the regulatory processes and policies needed to meet the challenges of regulating these complex products and coordinating their review and oversight. It has been my pleasure to serve at FDA during this next exciting period and to help ensure that the agency continues to prioritize this evolution by anticipating, responding to, and encouraging scientific advancements.

I am very pleased to be able to present a new report by FDA as part of our ongoing efforts in this field. Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development describes many of the exciting developments and looming advances in personalized medicine, lays out the historical progress in this field, and examines FDA’s regulatory role: from ensuring the availability of safe and effective diagnostic devices, to addressing the challenges of aligning a drug with a diagnostic device, to post-market surveillance.

Outside collaboration and information sharing is essential for this field to flourish. On Tuesday, the American Association for Cancer Research and AdvaMedDX held a fruitful daylong conversation on personalized medicine to treat cancer. I was one of the speakers, participating in a conversation with Dr. Francis Collins, the head of the National Institutes of Health. Our discussion focused in part on current status of drug and diagnostic co-development and the challenges and potential of whole genome sequencing, where data can be collected on a patient’s entire genetic makeup at a reasonable cost in a reasonable amount of time.

FDA is committed to fostering these cooperative efforts, as it will require the full force of government, private industry, academia and other concerned stakeholders to maximize our efforts and fully realize the promise of personalized medicine. Our new report outlines that commitment, and helps chart the way forward so that more people can live long and prosper.

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

FDA Goes 3-D

By Steven K. Pollack, Ph.D., and James Coburn, M.S.

Dr. Steven Pollack (left) holds a 3D-printed RoboHand, a prosthetic for children with amnionic banding syndrome, an illness that can prevent fingers from developing in children. Research engineer James Coburn (right) uses the 3-D printer (background) in his work in the FDA lab.

Dr. Steven Pollack (left) holds a 3D-printed RoboHand, a prosthetic for children with amnionic banding syndrome, an illness that can prevent fingers from developing in children. Research engineer James Coburn (right) uses the 3-D printer (background) in his work in the FDA lab.

This Snap-Together RoboHand Prosthetic, sized for a small child, was created at FDA with a 3-D printer.

The Snap-Together RoboHand prosthetic was invented by South African carpenter Richard van As and made available for free on the Internet. Before printing, the hand can be individually sized, and all connecting pieces are also printed. The device can now be printed for less than $100.

A hospital in Michigan implants a 3-D printed medical device into a 3-month-old boy with a rare bronchial condition and saves a young life.

A man has 75 percent of his skull replaced with a 3-D printed implant.

3-D printing—the process of making a three-dimensional solid object of virtually any shape from a digital model—is making headlines these days, and the technology, once considered the wave of the future, is rapidly becoming part of the present.

It’s spurring innovation in manufacturing, dramatically reducing the time required to design new products and allowing designs to be built that were not possible before.

Here at FDA, we’re using it to expand our research efforts and expand our capabilities to review innovative medical products. In fact, 3-D printing is fast becoming a focus in our practice of regulatory science—that is, the science of developing new tools, standards and approaches to assess the safety, effectiveness, quality and performance of FDA-regulated products.

With 3-D printing, the conversion from a virtual computer model to a physical object can occur almost in real time. The printer translates virtual models into digital cross-sections for use as a blueprint for printing, laying down successive layers in different shapes.

FDA Research Engineer James Coburn operates a RapMan kit 3D printer.

James Coburn adjusts the tension on the feed mechanism for the ABS plastic filament that is the raw material for the RapMan kit 3D printer.

Two laboratories in the FDA’s Office of Science and Engineering Laboratories (OSEL) are investigating how the technology may affect the manufacturing of medical devices in the future.

At our Functional Performance and Device Use Laboratory we’ve developed and adapted computer-modeling methods to help us determine the effect of design changes on the safety and performance of devices when used in different patient populations. The 3-D technology enables us to tweak the design in ways large and small, and to see precisely how those tweaks will change both fit and functionality. In an era of increasingly personalized medicine, which involves the development of treatments that are tailored to an individual patient or a group that shares certain characteristics, including anatomical features, it helps us to fine-tune our evaluation of patient-fitted products.

At our Laboratory for Solid Mechanics we’re investigating how different printing techniques and processes affect the strength and durability of the materials used in medical devices. What we’re discovering will be valuable to our reviews of devices down the road; it will help us to develop standards and set parameters for scale, materials, and other critical aspects that contribute to product safety and innovation.

In August 2012, President Obama launched the National Additive Manufacturing Innovation Institute (NAMII), a national effort bringing together industry, universities and the federal government to provide innovation infrastructure to support new technologies and products created with additive manufacturing, the formal term for 3-D printing.

FDA has a long history of researching and regulating innovative technological practices. Regulators regularly review some of the newest technologies coming onto the market and, through our research, FDA has first-hand knowledge of these advanced techniques so we can evaluate advanced technology at an early stage—a crucial step in facilitating innovation and protecting the public health. We will continue to facilitate device innovation and keep on the cutting edge of technology and regulatory science to help ensure that the products we regulate are safe and effective.

To see more photos of how FDA is using 3-D printing technology, visit our Flickr photostream.

Steven K. Pollack, Ph.D. is Director of FDA’s Office of Science and Engineering Laboratories (OSEL) at FDA’s Center for Devices and Radiological Health. James Coburn, M.S. is a Research Engineer in OSEL.