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

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

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