Targeting Drugs for Rare Diseases

Marshall L. Summar, MD; Gayatri R. Rao, MD, JD


November 25, 2014

Editorial Collaboration

Medscape &

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Rare Diseases: Seeing More Zebras?

Marshall L. Summar, MD: I'm Marshall Summar, chief of genetics and metabolism at Children’s National Medical Center in Washington, DC.

I am here for Medscape Rare Diseases at the National Organization of Rare Diseases Orphan Products Breakthrough Summit. Today I am talking with Dr Gayatri Rao, director of the Office of Orphan Products Development at the US Food and Drug Administration (FDA).

Back in our medical school days we were told, "When you hear hoof beats, think horses." What has happened is that rare diseases have come to the forefront in medicine, and that herd of horses now has a few zebras. How is that affecting the landscape of therapeutics and the FDA's role?

Gayatri R. Rao, MD, JD: We are increasingly in a world of zebras. Sometimes I think that I live in a vacuum, because my world is all zebras and almost no horses. Increasingly in the routine practice of medicine, we are seeing more patients with rare diseases.

Part of the reason for that is an increase in the diagnosis of rare diseases. Before, we would cluster groups of patients into syndromes, and now we are realizing that there are actually different disease states.

Not only are more patients being diagnosed, but from a therapeutic standpoint, interest has increased in the development of therapies for rare diseases as a result of an increased understanding of genomics. We are able to target therapies, which has expanded interest in the treatment of rare diseases.

Dr Summar: As we develop new therapies for rare diseases, interest in identifying patients with rare diseases increases. Is this a trend that will continue?

Dr Rao: Yes. In my office, we incentivize the development of products for rare diseases. More than 30 years ago, getting a pharmaceutical company to focus on rare diseases was a Herculean endeavor. With so few patients, it wasn't a good business decision to go into that area, so Congress created incentives to promote the development of products for rare diseases.

Since the inception of those incentives through the Orphan Drug Act, we have seen a tremendous increase in the interest of companies to develop products for rare diseases. We are starting to see increased focus on developing targeted therapies for different diseases—some that are rare and some that are not rare.

Divvying Up Common Diseases

Dr Summar: When we talk about rare diseases, the trend with genomic research and genetic medicine is to take common diseases and divide them into smaller and smaller groups. Do you see that beginning to overlap with the rare disease development process?

Dr Rao: Certainly. A good example is lung cancer. Right now, non-small cell lung cancer is by no means a rare disease. A rare disease is defined in the law as a disease that occurs in fewer than 200,000 people in the United States. It includes diseases such as inborn errors of metabolism, which might have a few dozen patients in each disease, all the way to diseases such as ovarian cancer (which is pushing 200,000) and everything in the middle.

More than 200,000 people have non-small cell lung cancer, but we are now starting to see the development of specific targeted therapies—for example, epidermal growth factor receptor (EGFR)-positive targets. When you start looking at patients who are EGFR positive, the number is less than 200,000, and so all of a sudden EGFR-positive non-small cell lung cancer falls in the rare diseases category.

As the understanding of science and the development of targeted therapies evolve, diseases that have been considered common all of a sudden start to fall into the rare disease category.

Dr Summar: This will have an impact on every field of medicine. Moving forward, the lessons being learned from the orphan products group will be applied across the rest of the regulatory landscape and to medicine in general.

Dr Rao: That’s right. The advent of targeted therapies is relevant not only to rare diseases but to common diseases as well.

Dr Summar: We will obviously be looking at new models for how to prove that therapies work in smaller groups of patients. You are blazing some trails over there at the FDA.

Dr Rao: It is interesting. One of the challenges is studying a small population. Often there is heterogeneity in the patient population. If we know that molecular basis of the genetic defect, we can target the therapy towards that genetic defect, and then structuring a clinical trial around individuals with that genetic defect becomes more feasible.

Growth in Rare Disease Diagnostics

Dr Summar: It is a new way of thinking about drug and therapeutic development, as well as the whole diagnostic spectrum. That is another growing area. The landscape is evolving with genetic testing. In my field, every week there is a new test or a new panel. How do you see the growth in that area?

Dr Rao: This topic is very near and dear to my heart. My office's mission is to focus on the promotion of all products for rare diseases—not just drugs and biologics but medical devices as well. There is a tremendous growth and interest in the development of drugs and biologics for rare diseases, but there is less conversation about devices. We are talking about both diagnostics and therapeutic devices.

One of the biggest challenges for those of us in the rare diseases field is diagnosing a patient with a rare disease. We hear about patients going from doctor to doctor for years before they get the right diagnosis. This is because it's not only that physicians are thinking about horses rather than zebras, but also because we don't have the appropriate diagnostic methods. We don't have enough testing. This is an area that needs to be developed.

The Challenges of a Moving Target

Dr Summar: In the clinical world, there is a gray zone between the actual diagnostic test and the interpretation of it, particularly with whole exome and some of the new genomic technologies, when each patient has literally thousands of changes and we try to pick one. That must present some challenges from a regulatory standpoint.

Dr Rao: The whole regulatory landscape around diagnostics is an evolving issue, and it is something that the agency is focused on right now.

Dr Summar: The technology changes so fast that it is a moving target. That must be hard.

Dr Rao: That's right. That continues to present a challenge, and those challenges are present not only in diagnostics but in the development of therapeutics as well.

Dr Summar: I am going to ask you to pull out your crystal ball and think about what you see coming in the world of rare diseases and rare disease therapeutics. What trends are we going to see in the field in general?

Dr Rao: We are going to start seeing the development of more targeted therapies and more therapies for subpopulations of patients. It could reframe what we think of as rare and whether a subcategory of a disease is a separate disease unto itself. I would like to see growth in diagnostics for rare diseases. That is an area of real need.

Dr Summar: You are right on the money in saying that we are going to see a lot more development. We are going to see more pools with smaller numbers of patients. It is going to be an interesting time.

Thank you for taking the time to speak with us today. I would like to thank our physicians and readers. There will be many new developments coming along in the rare disease field.

Gayatri R. Rao, MD, JD, director for the Office of Orphan Products Development (OOPD), received her MD from the University of Medicine & Dentistry of New Jersey - New Jersey Medical School. Upon graduation from medical school, she went on to earn a joint JD from the University of Pennsylvania Law School, where she concentrated on healthcare and FDA-related issues, and a master's in bioethics from the University of Pennsylvania School of Medicine. Following law school, she worked for an international law firm in Washington, DC, focusing primarily on food and drug law and other healthcare-related matters, including matters related to orphan products. She then joined the FDA’s Office of the Chief Counsel where she provided advice on a wide range of issues related to medical devices, combination products, clinical trials, and human subject protection. She has brought her unique medical, legal/regulatory, and bioethical background to help move the OOPD rare disease mission forward.