FDA’s Viewpoint on Approvals Needs to Be Heard: Dr. Pazdur

ROCKVILLE, Md—Last September, medical oncologist Richard Pazdur, MD, became director of the Division of Oncologic Drug Products at the US Food and Drug Administration. Dr. Pazdur joined the FDA after 12 years on the faculty of the University of Texas M.D. Anderson Cancer Center, where his most recent position was professor of medicine and director of educational programs within the Division of Medicine.

In this interview with Patrick Young, ONI’s Washington Bureau Chief, Dr. Pazdur discusses the FDA’s oncologic drugs approval process and his goals as division director.

ONI: What is the specific mission of your division?

Dr. Pazdur: Basically, it is to review oncology drug products. We interact with investigators and the pharmaceutical industry looking at clinical trial design and clinical data, and discussing with them strategies for eventual drug approval. Our division looks at cytotoxic chemotherapies or hormonal agents for the treatment of cancer. Another division handles biologic products.

ONI: What are your personal goals as director of this division?

Dr. Pazdur: I want to provide the agency with more transparency to the outside world as to its goals and functions. To do that, I want to encourage greater participation of the agency in academic endeavors.

These would include participating with organizations such as the American Association for Cancer Research (AACR), the American Society of Clinical Oncology (ASCO), and the Oncology Nursing Society to inform their membership about FDA practices.

In addition, I want to have a greater dialogue with the cancer advocacy community. This is especially important when we discuss areas of patient benefit that come into play with the oncology drug approval process.

ONI: How would groups like ASCO and AACR get involved?

Dr. Pazdur: I want to interact with them in educational programs. An example of this was a program that we put on at the AACR meeting in San Francisco in March. We held a joint workshop on chemoprevention and endpoints in chemoprevention trials. We are exploring with ASCO the presentation of a program on clinical trial design and one to explain our reasons for approving or not approving specific drugs.

In addition we have talked with ASCO and AACR about publishing, in peer-reviewed journals, review articles generated by the FDA on the drug approval process as well as on specific drugs that have come before our Oncologic Drugs Advisory Committee (ODAC).

ONI: Do you think oncologists are interested in the review process?

Dr. Pazdur: Yes. Most of the people who attend the ODAC meetings are investors, drug company personnel, or others connected to the pharmaceutical industry. But I think most medical oncologists still have an interest in these meetings.

It is important for them to understand the differences between just demonstrating that a drug has activity vs showing that the drug has clinical benefit for the patient. By clinical benefit, I mean patients live longer or symptoms decrease or are prevented by the administration of the particular agent.

The pharmaceutical companies have ample opportunity to publish results of their own clinical trials. We look at our presentations as being somewhat different. Many times, our presentations combine all of the known clinical material—combined clinical trials, looking across clinical trials for trends, for patient benefits, etc—whereas most of the information from a company deals with a specific clinical trial.

We realize that medical oncologists do not rely heavily on the package inserts, or drug labels, even though the FDA spends a great deal of time writing these labels. This is why we would like to use articles in peer-reviewed journals to get our viewpoint across, as well as our concerns and the rationale for specific drug approvals.

ONI: What other goals have you set for yourself as director?

Dr. Pazdur: I would like the ongoing dialogue with the academic community and cooperative groups to include several other important issues, including endpoints in chemoprevention, as mentioned previously, surrogate endpoints, and quality of life.

Measurement of quality of life in clinical trials needs a great deal of research and exploration, because it brings in the patient aspect of the benefit of the drug. The clinical trials community has a poor understanding of how we can use the various tools for measuring quality of life and how drugs may affect quality of life.

We have an ODAC subcommittee assessing quality of life. It is an ongoing dialogue we are going to have this year and perhaps next year. That is a very difficult issue that is not going to be answered by one or two meetings.

ONI: Do you have other areas that you intend to look at with special ODAC subcommittees?

Dr. Pazdur: One of the others is a special pediatrics subcommittee. We have recently outlined a plan for the industry and interested parties to develop new pediatric oncology drugs. We believe the pediatric oncology community has not been well represented in the drug approval process. We want to emphasize the early development of drugs in pediatrics. One of my efforts is to hire more pediatric oncologists to look at these applications.

ONI: What changes would improve the ODAC process?

Dr. Pazdur: We would like to have more ODAC meetings where we discuss scientific issues rather than a particular drug application—for example, to discuss an endpoint such as time to progression vs survival in a particular disease, or how to handle certain clinical trial methodology issues.

ONI: Will we see more surrogates or nontraditional endpoints used to determine drug efficacy?

Dr. Pazdur: What we are looking for in endpoints, basically, is reliability—consistency in their measurement and how well they predict clinical benefit. Although we have generally looked at survival and amelioration of disease-related symptoms, we are open to looking at other endpoints, particularly as new classes of drugs are developed.

For different agents such as hormones, we have taken a look at time to progression as an endpoint, and we have surrogate endpoints for accelerated approval for a variety of drugs.

The most important thing is the magnitude of change in these surrogate endpoints. If we are talking about very small changes, it becomes uncomfortable for us to approve a drug. However, if the magnitude of change is very compelling, then we would be much more willing to examine these as endpoints for approval.

ONI: What do you see happening in the issue of off-label cancer drug use?

Dr. Pazdur: I think the agency has to realize that oncology is much different from other areas of medicine such as cardiology. Off-label use of drugs is extremely common in medical oncology, and it probably represents more of the rule than the exception.

Medical oncologists, just by their training, are more likely to act as clinical trialists because of the seriousness and life-threatening nature of many of the diseases they treat. Medical oncologists in the community are willing to alter doses and schedules to either reduce toxicity or, in their minds, increase efficacy.

The discipline of medical oncology is basically a pharmaceutically driven specialty. We deal with a vast number of patients with life-threatening diseases, and we have very marginal or suboptimal treatments for them. The agency has to take into account what is happening in the real world rather than trying to dictate how oncologists will practice, because they will practice in what they regard as the best interest of their patients.

ONI: Will you push the industry to seek approval of some of these off-label uses?

Dr. Pazdur: We would like them to do so. However, it is going to be very difficult, and I am not sure if it will be realistic for them to include in the label all the ways an individual drug is administered. Drugs in oncology, once they are approved, take on a life of their own. They are used in numerous doses, schedules, and administration realms.

ONI: From the FDA perspective, what changes are needed in the review system?

Dr. Pazdur: Mechanistically, we need to expedite especially interesting compounds and speed up the review process. I would also like a joint medical-statistical review of a particular application, rather than the two disciplines reviewing the application separately. I would like to take a closer look at endpoints in particular diseases. And, as I alluded to before, we are open to discussing the increasing use of surrogate endpoints.

ONI: Once ODAC makes a recommendation on a drug, who in FDA actually makes the decision?

Dr. Pazdur: After ODAC votes, we have internal meetings, and a consensus of opinion is reached among the medical team that has reviewed the drug, the division, myself, and the Center for Drug Evaluation and Research as to whether or not to approve the drug. We may or may not follow the ODAC vote, but we put a great deal of weight on what ODAC says.

ONI: Some have expressed concern that many of the drugs approved by FDA have little additional benefit over available drugs. Is FDA approving too many “me-too” drugs?

Dr. Pazdur: We can only evaluate the applications submitted to us. Perhaps this trend toward “me-too” agents is more a reflection of what is going on in the pharmaceutical industry with the tendency to want a safer investment. In other words, it is easier to follow a pattern formula than to break out and develop a truly novel agent. However, analogs that reduce toxicity, such as mucositis or neutropenia, while maintaining the efficacy of a particular class of drugs, are useful for patients.

We would all like blockbuster drugs, but we have to be realistic. Gains in oncology are often incremental.

ONI: Finally, the accelerated approval process requires phase IV post-marketing studies. Are companies pursuing these adequately in your opinion?

Dr. Pazdur: Yes. We are very serious about the phase IV commitments that companies make to us. They are binding commitments, and failure to perform the required study or poor performance of the product could result in eventual market removal of these products. Pharmaceutical companies should be on notice of this.