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

Supporting Innovative Research Through Regulatory Science

By: Carolyn A. Wilson, Ph.D.

In my last blog post I discussed aspects of regulatory science, that is, how scientists in FDA’s Center for Biologics Evaluation and Research (CBER) help to turn innovative medical research into life-saving or life-enhancing biological products. I also described how FDA scientists help determine if potential health problems are linked to the use of a particular medical product. In this post, I’ll discuss two more studies that made important contributions to public health.

Carolyn WilsonSometimes CBER research changes the way scientists look at a problem so their research is more efficient. For example, in the field of gene therapy, a strain of the common cold virus called an adenovirus, is used as a vector – delivering therapeutic genes to treat both inherited and non-inherited conditions. However, success of this therapeutic approach has been hampered in part by the finding that an immune response to the adenovirus may prevent efficient delivery of the therapeutic genes to their targets, such as cancer cells. The problem appeared to be that once inside the body, the adenovirus attaches a blood clotting protein called FX to itself and binds to liver cells. As a result the vector doesn’t reach the desired target cells where it would deliver the therapeutic gene.

Some scientists thought that altering the virus so it couldn’t bind FX would let it avoid the liver, making it a more efficient vector. However, scientists in the Office of Cellular, Tissue and Gene Therapies (OCTGT) discovered that adenovirus commandeers the FX protein to use as a shield to evade attack by the immune system. So removing it would likely enable the immune system to attack and disable the adenovirus and block treatment. This new knowledge that the adenovirus needs FX to disguise itself from the immune system will help guide researchers to design gene therapy vectors that survive in the bloodstream and reach their desired target cells.

Another group of scientists, in the Office of Blood Research and Review (OBRR), has contributed to our understanding of why African Americans are significantly more likely than whites to produce antibodies against a drug used to treat hemophilia A. People with hemophilia A carry a mutation in the gene for the protein Factor VIII (FVIII) – a protein that plays an essential role in clotting and preventing blood loss. This mutation either eliminates or greatly reduces the amount of Factor VIII in the blood. Fortunately, there is a therapeutic form of FVIII made through biotechnology that is used to replace faulty or missing, natural FVIII. But unfortunately, some African Americans with hemophilia A make antibodies against therapeutic FVIII. These antibodies attack it and disrupt treatment. The FDA scientists discovered certain genetic variations in the gene for Factor VIII made by these individuals that appear to be responsible for this immune system attack. The discovery is an important step in developing ways to predict which patients will develop antibodies against this complication. And that is an important step toward developing a personalized-medicine approach to hemophilia A by custom-designing medical responses to this life-threatening disease.

The examples I’ve given of CBER research here and in my previous blog are just a small sample of the important knowledge our scientists are creating that supports efforts of medical researchers striving to develop products that improve public health nationally and globally.  In 2013, CBER scientists published their research findings in over 200 journals and books.

I’ll be back to update you on more exciting research from CBER during 2014.

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

Regulatory Science Supports FDA’s Regulatory Mission

By: Carolyn A. Wilson, Ph.D.

You might only think of FDA as a regulatory agency that oversees medical and food products. But FDA scientists, including those in the Center for Biologics Evaluation and Research (CBER), also perform research. In this first of two blog posts, I will describe how regulatory science, as it is called, helps to turn innovative medical research done at FDA and other places into life-saving or life-enhancing biological products.

Carolyn WilsonMost of the discoveries made at CBER support the development of new or improved vaccines, blood and blood products, and tissue, gene and cell therapies. This research also helps CBER make very informed decisions about new products and policies. That’s because many of the same CBER scientists whose research puts them at the cutting edge of science also review potential new products, inspect commercial facilities that make products, and help develop new policies and guidance documents for industry. In the past year, discoveries that CBER scientists have published in research journals have contributed significantly to public health by addressing issues that affect the safety and effectiveness of vaccines, gene therapy, and a treatment for a serious blood disorder.  

For example, scientists in the Office of Vaccines Research and Review (OVRR) took a big step in solving the mystery of why the rates of pertussis (whooping cough) in the United States have been increasing since the 1980s – despite widespread use of a pertussis vaccine. OVRR scientists showed in baboons that even though the vaccine can prevent symptoms of pertussis, animals receiving it still had the bacteria that cause the disease in their airways for up to six weeks.

These animals were then able to spread the bacteria to other animals. This suggests that while the vaccine protects children from getting pertussis symptoms, vaccinated children can still spread the bacteria through coughing to other children for several weeks – especially if those children aren’t vaccinated. This information is important because it can help scientists and public health officials design new vaccines and strategies to reduce the rate of pertussis in the US.

Statisticians and epidemiologists at CBER also make critical contributions to regulatory science. Serious adverse medical events sometimes occur in patients treated with licensed products (i.e., vaccines). When physicians or consumers report such events to the FDA, epidemiologists at the agency work to determine whether these events are actually caused by the licensed product or are just a coincidence. For example, epidemiologists and statisticians in the Office of Biostatistics and Epidemiology (OBE) studied whether getting the vaccine for 2009 H1N1 influenza (the so-called “swine flu”) several years ago increased the risk of developing a nerve disease called Guillain-Barré Syndrome (GBS). GBS can sometimes occur after infections or vaccinations, causing weakness in the arms and legs and reducing reflexes. The concern about the 2009 vaccine was based on the occurrence of GBS over 30 years ago among some people who received the vaccine against a related strain of H1N1 virus in 1976. CBER’s epidemiologists asked whether the more recent vaccine used to protect against the 2009 H1N1 virus also increases this risk. To answer this question, OBE researchers reviewed the medical records of 23 million individuals who received the 2009 H1N1 influenza vaccine during the 2009-2010 influenza outbreak. Their statistical analysis showed that the risk of death or hospitalization from H1N1 infection was about 500 times greater than the risk of developing GBS from the vaccine. 

Studies like these are very important because they help FDA regulators and public health officials to determine whether potential adverse effects are actually linked to the use of a particular product. In this case, confirming the safety of the vaccine was an important public health measure because it reassured the public that this vaccine was safe to take. 

In my next blog post I’ll be discussing important contributions CBER scientists recently made to gene therapy and the treatment of a blood disease called hemophilia. 

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