A Look Ahead: How the FDA Is Adapting in the Era of Precision Medicine
A Conversation With Richard Pazdur, MD
Dubbed “Cancer Czar” by the media, Richard Pazdur, MD, Director of the U.S. Food and Drug Administration (FDA) Office of Hematology and Oncology Products, said he has the “best job in oncology, with a unique vantage point in cancer drug development.” An oncologist for more than 30 years—including 14 years at the FDA—Dr. Pazdur’s commitment to the agency comes at an unprecedented time in the development of more effective oncology drugs and faster drug approvals. As of August 2013, 7 of the 15 new drugs approved by the FDA this year are used to treat or diagnose cancer.
Under Dr. Pazdur’s leadership, the FDA has used different regulatory mechanisms, including Priority Review, Accelerated Approval, and Fast Track designations, to speed the development and approval of promising new oncology drugs. A provision in the FDA Safety and Innovation Act of 2012, the new Breakthrough Therapy designation for treatments for serious or life-threatening diseases is designed to improve communication and collaboration between the FDA and the pharmaceutical industry to quicken drug development and the review of marketing applications.
ASCO recognized Dr. Pazdur for his dedication to improving the lives of patients with cancer through the approval of safer, more effective medicines with its 2013 Public Service Award, which was presented at ASCO’s Annual Meeting in June.
In a wide-ranging interview, The ASCO Post talked with Dr. Pazdur about the Breakthrough Therapy drug designation, how the development of molecularly targeted therapies is altering the design of clinical trials, his role at the FDA, and his advice to young oncologists considering a career in public service.
Please explain the new process for expediting the development of oncology drugs given Breakthrough Therapy status?
The Breakthrough Therapy designation is given to drugs that are intended to treat a serious or life-threatening condition when preliminary clinical evidence indicates that the drug might demonstrate a substantial improvement over existing therapies on a clinically significant endpoint.
Breakthrough Therapy status provides for enhanced communication between the drug sponsor and the FDA throughout the drug development process rather than at conventional milestone meetings, such as pre-IND or end-of-phase II meetings. Drug development becomes an iterative process, with an “all hands on deck” commitment at the FDA. This involves our senior leadership and members of the review team including clinical, biostatistics, clinical pharmacology, pharmacology-toxicology, and chemistry staff and their counterparts in industry.
We are communicating with the sponsor and providing advice on trial designs and discussing potential issues—both clinical and nonclinical—that if addressed earlier in the drug development timeline may expedite the drug’s approval. Approximately half of the Breakthrough Therapies that have been designated by the agency have been in oncology, reflecting the activity of drug development in our discipline.
Evolution of Study Designs
Looking ahead over the next 5 to 10 years, do you see the design of clinical trials changing so as to test targeted drug regimens in small subsets of patients?
Yes, the designs of trials are changing, reflecting the greater efficacy of many oncology drugs that are currently being developed. With a transition from conventional chemotherapy to more targeted therapies, we are evaluating drugs that provide greater efficacy with a more favorable toxicity profile.
These newer agents may target diseases in specific populations and assist in redefining oncologic diseases and indications based on our enhanced molecular understanding. In an era of more personalized or precision medicine, early identification of patients with specific biomarkers or companion diagnostics will be required.
We probably will see smaller randomized clinical trials since the treatment effect of a targeted agent will probably be larger than that observed with conventional chemotherapy agents. To demonstrate a statistically significant therapeutic effect that is relatively small, a larger number of patients is usually required. Generally, to see a larger therapeutic effect, a smaller number of patients is required.
We also need to develop and implement adaptive clinical trial designs that take into consideration information that is being developed during the conduct of the trial. The goal is to provide the most efficient trial to demonstrate an improvement in efficacy while limiting the number of patients who may be exposed to a less effective drug.
Will overall survival continue to be required to approve drugs?
Although overall survival has been traditionally considered the “gold standard” for drug approval, we have recognized that it may be increasingly difficult to demonstrate an improvement in overall survival. Hence, the FDA has increasingly accepted progression-free survival as a regulatory endpoint. This might be the case in situations where the natural history of the disease is relatively long, making overall survival impractical to measure, or in situations where multiple therapies are administered after disease progression, possibly confounding the overall survival interpretation.
Role of Randomized Trials
Will the ability to identify and validate biomarkers, enabling the matching of investigational drugs with patients who will most benefit and/or be least likely to experience adverse effects, render the traditional randomized clinical trial model obsolete?
There will always be a role for randomized trials to evaluate both drug safety and efficacy. Randomized trials provide important comparative safety information. Single-arm trials do not provide this information. Time-to-event endpoints, such as progression-free survival and overall survival, need to be evaluated in randomized trials.
However, there may be clinical situations where conducting a randomized trial may be impractical—for example, if a large unmet medical need exists, and a drug has demonstrated an unprecedented response rate of long duration in a single-arm trial. Randomized trials should only be performed in the setting of clinical equipoise of the treatment arms. If equipoise does not exist, then one should question whether this specific randomized study can or should be conducted.
Please discuss the best solution for evaluating and approving biosimilar proteins.
Drug companies need to approach the development of biosimilars differently than “stand-alone” product development. The goal is to demonstrate biosimilarity between the proposed product and a reference product—not to independently establish safety and effectiveness of the proposed product. Understanding the relationship between protein attributes and the clinical efficacy and safety profile aids in the ability to determine residual uncertainty and to predict “clinical similarity” from the quality data.
The FDA has stated it intends to use a risk-based, totality-of-the-evidence approach to evaluate all available data and information submitted to determine the biosimilarity of a proposed product. Advances in analytic sciences and manufacturing technology have enabled some therapeutic protein products to be extensively characterized with respect to their physicochemical and biologic properties. This may provide an appropriate basis for a more targeted approach to subsequent animal and/or clinical studies for a demonstration of biosimilarity.
Impact of Sequestration
How is sequestration affecting the FDA, and does it have the potential for slowing drug approval?
I really can’t comment on the effect sequestration may have on drug approval. However, the FDA has been under travel restrictions that have prevented many of our reviewers from attending important meetings, including ASCO’s Annual Meeting. For our reviewers to give advice on the development of new drugs, they must have continuing education and communication with our stakeholders, including oncologists in academic and private practice settings, professional societies, commercial sponsors, and patients.
Rewards and Challenges
What is the most rewarding and challenging aspect of your job?
The most rewarding part is mentoring our young staff. One of my greatest pleasures is to see their enthusiasm, especially that of our review staff who have joined FDA shortly after completing their fellowships. Early in my career, I was the Medical Oncology Fellowship Director at Wayne State University in the 1980s and at MD Anderson Cancer Center in the 1990s. I have always had an interest in medical education, and one of the true highlights of my career has been seeing “my fellows” become leaders in academic oncology centers.
In terms of challenges, I’ve been at the FDA long enough to realize that we’re not going to make everybody happy with our decisions. For every decision, there is going to be a group who believe we made the wrong decision and a group who applaud the decision. Frequently, I hear investigators and others outside of the FDA mischaracterize our positions without having access to FDA documents or discussions. Many times, these comments may result from the FDA’s inability to comment on unapproved drugs because of government confidentiality requirements regarding information disclosure.
Within FDA, we spend considerable time reviewing an application and discussing the strengths and weaknesses of each application. I fully understand that there is no such thing as a “perfect” clinical trial. At the end of the day, I tell the staff that we must ultimately ask ourselves the question, “Will the American public be better served with the drug on the market?”
FDA and NCI
What is the FDA’s relationship with the National Cancer Institute (NCI)?
We have a very good relationship with the NCI—better than any other government agency. Our mutual goals are aligned. We have monthly meetings where we review common drug development issues. We collaborate with the NCI in developing programs and workshops. Many of our staff have worked at the NCI and have completed their training at the National Institutes of Health (NIH)/NCI Clinical Center. Many FDA staff members also have a professional development day at the Clinical Center to improve and continue development of their clinical expertise.
Is there anything you would like to communicate to readers of The ASCO Post regarding the FDA’s goals for the future of cancer care?
We are on the same page as the treating oncologist. We all want safe and effective drugs to treat patients with cancer. There is always a diversity of opinion, and every opinion is heard, but at the end of the day, a decision has to be made.
This is a great time to be a medical oncologist. There may be day-to-day frustrations, but we are experiencing unprecedented growth in our understanding of cancer, and this is being rapidly translated into new drugs. Having had a more-than-30-year perspective as a medical oncologist, I firmly believe this is the most exciting time in that 3-decade experience. I envy those who are just beginning their careers because they may truly witness quantum leaps in cancer therapeutics.
One issue I would like to address concerns expanded access (access to investigational drugs outside of a clinical trial), because I believe there may be questions and misconceptions about this program. Several times we have heard erroneously that the FDA has refused to give an investigational agent to a patient or allow an expanded access trial when, in reality, the pharmaceutical sponsor did not permit the release of the drug.
We at the FDA strongly believe in early access to promising drugs for patients who need them. Various regulatory mechanisms exist that enable patient access to unapproved drugs outside of a clinical trial, including single-patient investigational new drug (IND) applications as well as intermediate-size and large-population treatment expanded access programs. We have worked with ASCO on education programs to provide information about expanded access.
The FDA does not have the authority to compel a pharmaceutical company to give a drug to an individual patient or to have a large expanded access program. We have asked ASCO to develop a policy at the Annual Meeting asking pharmaceutical companies to declare their intentions—positive or negative—regarding expanded access programs when promising results of unapproved drugs are presented. This, along with the company’s rationale for its decision, would provide clarity for patients and physicians and provide transparency on the process.
What advice would you give to young oncologists who may be considering a government career?
Public service is an extremely rewarding career. When I left MD Anderson Cancer Center in 1999, I thought I would be at the FDA for a few years at most. Well, obviously, I was wrong. I have really enjoyed myself and, most importantly, I have enjoyed working with great staff on interesting issues that have fashioned the field of oncology over the past 14 years. Virtually every problem in oncology drug development crosses my desk.
At the FDA, we have a public health mission, and as a medical oncologist you can have an impact on the lives of potentially millions of patients in the United States and worldwide. I would encourage young oncologists to come down and see us if they have an interest in public service. ■
Disclosure: Dr. Pazdur reported no potential conflicts of interest.
1. September 30, 2013: Pertuzumab (Perjeta) Accelerated approval in combination with trastuzumab and docetaxel for the neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early-stage breast cancer.
2. September 6, 2013: Paclitaxel protein-bound particles (albumin-bound)...