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

“Breakthrough” Designation … Another Powerful Tool in FDA’s Toolbox for Expediting the Development and Review of Promising New Drugs for Serious Conditions

By: Janet Woodcock, M.D.

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

In fiscal year 2012, FDA approved 35 novel new drugs, also known as “new molecular entities.” Among these new products were drugs to treat patients with unmet medical needs, such as a groundbreaking treatment for a form of cystic fibrosis, the first FDA-approved human cord blood product for hematopoietic reconstitution, used to help patients with blood forming disorders, and the first drug to treat advanced basal cell carcinoma (a form of the most common skin cancer).

To enable our ongoing efforts to bring innovative drug products to the public as efficiently as possible, FDA relies heavily on several expedited development and review tools such as fast track designation, the accelerated approval pathway and priority review designation. For instance, 56 percent of the novel drugs approved by the Center for Drug Evaluation and Research in calendar year 2012 used some combination of these tools to speed promising therapies to patients with serious conditions. And any given drug may have received multiple expedited program designations. (See a brief summary of how each of these tools helps FDA shorten the development and review of promising new therapies.)

In July 2012, a provision in the new law called the Food and Drug Administration Safety and Innovation Act, or FDASIA for short, gave FDA another powerful expedited development tool, known as the “breakthrough therapy” designation. This new designation is now helping FDA assist drug developers expedite the development of new drugs with preliminary clinical evidence that indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. Although the designation is not yet even a year old, FDA has received 62 requests to grant this new designation to products under development. We have been very active on this subject, meeting with companies and discussing ways to expedite the drug development process for drugs that show striking early results. We have already granted the breakthrough designation to 20 potential innovative new drugs that have shown encouraging early clinical results.

Drug developers should have a clear understanding of all of FDA’s expedited development and review tools. To help industry better understand each tool, including when the tools can be used and the features of each, we have just published an industry draft guidance titled Expedited Programs for Serious Conditions — Drugs and BiologicsAmong other important information, the draft guidance describes FDA’s policies and the threshold criteria for each expedited program, defines and discusses important concepts, including serious condition, unmet medical need, and available therapy, and provides some general considerations for products utilizing an expedited program, such as manufacturing and product quality, nonclinical considerations, and clinical inspection considerations.

The breakthrough therapy designation gives us another tool in our “toolbox” to help expedite the development and review of new drugs to treat patients with serious medical conditions and little or no treatment options. We’ll continue to use the new breakthrough therapy designation and our existing tools to help make our expedited programs even more effective.

We’ve said it before — and I believe it’s worth repeating — our decision-making on whether to approve a drug always involves an evaluation of many factors, such as the seriousness of the disease.  However, ultimately any drug approved must show that its benefits outweigh its risks and regardless of which expedited development or review program or programs are used, FDA does not compromise its safety or efficacy standards in exchange for rapid approval. Like all drugs we approve, those approved after having been designated as breakthrough therapies will meet our usual rigorous standards for safety and effectiveness.

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

Strategies for More Successful Drug Trials

By Bob Temple, M.D.

Bob Temple, M.D.  is Deputy Director for Clinical Science in FDA’s Center for Drug Evaluation and Research

Bob Temple, M.D., Deputy Director for Clinical Science

In recent months, drug developers have succeeded in bringing important drugs to market for cystic fibrosis, cancer and other conditions by employing strategies for achieving greater clinical trial success.

Today FDA is issuing a draft guidance that spells out how drug developers can use such strategies, known as clinical trial enrichment, to greatly increase the likelihood that data collected during a clinical trial will demonstrate that an effective drug is effective. These are potentially powerful strategies for the pharmaceutical industry because appropriate use of enrichment could result in smaller studies, shortened drug development times, and lower development costs.

Here’s how it works. Before any promising drug can come to market in the United States, drug developers must provide sufficient evidence that the product is safe to use on patients (that is, that the benefits of the drug outweigh its known risks), and is effective in treating a specific disease or medical condition.

Evidence is typically collected by enrolling patients in a clinical trial and then randomly assigning them to two groups: one group that will receive the drug and the other group that doesn’t.

Those who employ an enrichment strategy enroll patients who are likely to demonstrate an effect, based on their demographics, clinical histories or other characteristics.

Anyone familiar with clinical trial selection knows that rudimentary enrichment strategies have long been common. After all, investigators don’t simply study a random sample of the overall population. Instead they try to find a population most suitable for studying the drug.

One way to do this is to decrease what might be called “noise.” For example, including people who don’t really have the disease being studied, or including people who won’t take the medicine or complete the study, will make an effect harder to show.

There are two other kinds of enrichment: prognostic enrichment and predictive enrichment. Prognostic enrichment involves choosing patients for a study who will have the disease manifestations the drug is intended to prevent. For example, a study of a lipid-lowering drug intended to decrease the rate of heart attacks might choose a population likely to have an increased risk of heart attacks, such as being diabetic. Choosing patients of that kind makes it more possible to see an effect if there is one.

Predictive enrichment is particularly exciting and involves use of some aspect of the patient’s physiology, genetics or past responses to identify patients who can respond to the treatment.

Conducting a clinical study in a patient population that has a larger than average response to treatment can greatly reduce the number of patients needed in the study and can direct the treatment to the patients in whom the drug actually works.

The cystic fibrosis drug Kalydeco (ivacaftor) is an example of this successful strategy. The drug works only in the 4 percent of CF patients with a specific genetic abnormality. If the drug had been studied on the entire CF population, it would have been impossible to detect the drug’s effect.

An enrichment strategy was also used successfully in studies of of Xalkori (crizontinib) for patients with a late-stage form of lung cancer.

While enrichment won’t save a drug that doesn’t work, it will help find one that will.

Bob Temple, M.D., is Deputy Director for Clinical Science in FDA’s Center for Drug Evaluation and Research

How Science and Strategic Collaboration Led to a New, “Personalized” Cystic Fibrosis Treatment for Some Patients

By: Janet Woodcock, M.D.

Targeting a drug for small subgroups of patients is a new way to find effective therapies. This is often called personalized medicine, and it’s one of today’s most promising areas of new drug development.

Last year, FDA approved two important targeted medicines: Xalkori (crizotinib), a lung cancer drug that targets tumors with the abnormal ALK gene, and Zelboraf (vemurafenib), a drug to treat malignant melanomas that have a certain gene mutation. Both drugs were approved with companion diagnostic tests to identify if patients have a susceptible tumor.

Today, the FDA approved Kalydeco (ivacaftor) to treat a specific subgroup of patients with cystic fibrosis (CF). Cystic fibrosis is an inherited genetic disease that affects a person’s lungs and other organs and may lead to an early death.

Janet Woodcock, M.D.What makes the availability of Kalydeco even more unique is that the drug’s developer, Vertex Pharmaceuticals, teamed up with the Cystic Fibrosis Foundation to develop and study the drug.

This success story began in 1989 when a team of researchers, including Francis Collins, now the director of the National Institutes of Health, discovered the gene that is involved in cystic fibrosis. This gene, known as CFTR, plays an important role in producing a protein that regulates the flow of salt and water out of the cells that line the cavities of the body. There are a number of different mutations that can cause the CFTR gene to produce a defective protein. This results in lung congestion and digestive problems.

Kalydeco targets a gene mutation that only occurs in about 4 percent of CF patients. Before using this medicine, doctors will test CF patients to determine whether they have this mutation (many CF patients have already been tested to understand what caused their CF).  If the patient is a match, the drug may provide substantial benefits including improved lung function and weight gain.

Patients have played an important role in how new drugs are developed and studied since the HIV/AIDS activists in the 1980s and 1990s. But what the Cystic Fibrosis Foundation pioneered is a new form of patient power that some have called venture philanthropy. The Foundation helped with a portion of the drug’s development costs, provided researchers with useful insights about the CF patient population and helped in the recruitment of study participants – contributions that were critical to quickly bringing the innovative new therapy to patients.

The unique and mutually beneficial partnership that led to the approval of this new therapy for some CF patients serves as a great model for future drug development and patient group collaboration moving forward.

Here’s to innovation and continued cooperation and progress for patients!

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