Tag Archives: Cystic Fibrosis

Strategies for More Successful Drug Trials

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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Today FDA is issuing a draft guidance that spells out how drug developers can use such strategies, known as clinical trial enrichment, to greatly increase the likelihood that data collected during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

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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