2019

Prepared Remarks:
Richard Pazdur, MD
Director, Oncology Center of Excellence U.S. Food and Drug Administration

2019 is a banner year for me. I started oncology in 1970, so I’m celebrating my 40th anniversary as an oncologist. I started at the FDA in 1999, so this is my 20th anniversary at the Agency.

I thought I would reflect on what oncology looked like in the late 1970’s.

I remember…

I remember the time when the only treatment for renal cell carcinoma was Megace, a progestin.

I remember a time when the only treatment for multiple myeloma was melphalan and prednisone and the only treatment for melanoma was DTIC.

I remember going to a friend’s funeral who died of chronic myelogenous leukemia at the age of 35 after receiving the only known effective therapy—busulfan and hydroxyurea.

I remember a time when AIDS did not exist.

I remember when women with breast cancer were treated with radical mastectomies.

I remember a time without taxanes, Herceptin, aromatase inhibitors.

When I started in oncology, I had misconceptions of what the field would evolve into. My 1979 binoculars focused on the following beliefs. I could have NOT been more WRONG.

My 1979 Belief: The vast majority of patients with cancer would be treated at academic medical centers and every patient would be enrolled on a clinical trial, because our treatments were so modest.

I believed that the vast majority of drugs would be discovered and developed by the NCI and commercial pharmaceutical companies would have little interest in the oncology. Why? Oncology was associated with excessively toxic drugs of little benefit to patients and were used for short time periods that would not support a viable economic model.

These were my 1979 optics. Fast forward—2019.

2019 Reality: The vast majority of patients are treated in the community setting, not in academic centers. Less than 5% of patients are entered on clinical trials. Oncology is the (yes, the) most active area of drug development for the pharmaceutical industry reflecting 40% of total pharma activity. Fifty percent of our breakthrough designations are in the area of oncology. We have not only a large number of drugs being developed, but these drugs hold the potential for significant therapeutic advances.

We have witnessed dramatic changes on how some cancers are treated yet have not observed these changes in other cancers.

How did we get here? What forces shaped this period of time? What part did the FDA have in 2019 reality? My story:

The most important underpinning of any success is the scientific discovery of important drugs based on our understanding of biology of the malignant disease and how drugs interact with targets. Most recently, we have gained a greater understanding of how to manipulate the human immune system with PD-1 and other checkpoint inhibitors. This is rational drug development based on the foundation of scientific discovery.

In contrast, throughout much of my career, cancer drug discovery focused on what I call “roulette wheel” drug discovery.

Drugs would be discovered on the basis of anti-proliferative activity, tested in phase 1 trials to determine a maximum tolerated dose, and then evaluated in a variety of tumor sites, based either on a glimmer of activity observed in phase 1 trials or on economic models of high prevalence tumors that would recoup economic investment.

We—as a discipline—accepted a different safety profile coining terms, such as “manageable toxicity” to reflect aggressive approaches to deal with severe and life-threatening toxicities.

Then came 2001 and the approval of imatinib or Gleevec for CML. Not the proverbial “needle in the haystack” approach to drug discovery, but a drug based on a true molecular target revolutionizing the treatment of CML—but more importantly, demonstrating a tailored drug based on our understanding of the disease providing a conceptional framework for other drugs.

This targeted approach has been extended to other malignancies, including redefining lung cancer into molecular definitions of disease based on ALK rearrangement, EGFR mutations, ROS 1 rearrangement, PD-1 high. In essence, we redefined lung cancer based our greater understanding of the disease, armed with therapies directed at these targets.

In addition, important advances have been made in renal cell cancers, melanoma, and myeloma.

These treatments have been extended in earlier, adjuvant setting, similar to those principles pioneered in breast cancer decades ago, extending the potential benefit of cure to high-risk patients.

What is the role of FDA in a rapidly changing scientific and clinical environment?

The Agency must be cognizant of both the changing scientific environment, but also evolving societal expectations regarding the involvement of its citizens in decision-making.

In the end, the FDA is a public government agency ultimately answering to the US public charged with protecting and promoting the health of the American public, and the Agency must establish a balance between protection and promoting public health.

In the past 57 years since the 1962 amendment to FDA regulations, we have witnessed massive social issues facing our country. We have fought unpopular wars, such as Vietnam. We have witnessed social movements of racial and gender equality.

One unifying feature of these movements has been a greater demand of citizens to have a voice in government decisions.

Nowhere was this pressure more pronounced than with the AIDS activists of the late 1980’s to apply pressure on FDA to develop a more flexible regulatory environment responsive to the needs of patients.

This activism from the AIDS community resulted in our Accelerated Approval regulations. Although Accelerated Approval had its origins in HIV infections, these regulations are now predominantly used in the area of oncology.

Our endpoints for clinical trials have evolved based on changing benefit-risk evaluation for oncology drugs based on our discussions with external stakeholders.

In the 1980’s, after discussion with the Oncology Drug Advisory Committee or ODAC, FDA determined that the approval of drugs should be based on improvements in overall survival, due to the perception that oncology drugs had modest activity with marked toxicity.

Jump to the new millennium:

With the advent of targeted therapies, it became apparent that a re-evaluation of the dogma that overall survival was the only acceptable endpoint was needed.

First, for drugs demonstrating unprecedented response rates in early clinical trials in cancers with few therapeutic options, the ability to randomize patients to either a drug with markedly improved durable response rates versus a toxic marginally effective drug may not be possible.

Equipoise—a concept inherent in the randomization process—may not exist.

If a randomized trial is conducted in these situations, investigators and patients requested cross-over to the investigation drug that had demonstrated early impressive activity.

This crossover may confound the demonstration of an improvement in overall survival, because patients in both arms receive the same overall treatment—although it may be administered in a different sequence.

A demonstration of an improvement in overall survival may also not be practical in cancers with long natural histories or due to advances in our therapies.

Other cancers have limited numbers of patients and randomized trials powered to detect an improvement in overall survival simply may not be feasible due to the small number of patients.

This is increasingly more common as we divide diseases into molecular subsets.

These three features—high activity in early clinical development compromising equipoise in randomized trials, the long history of diseases, and the rarity of cancers due to reclassification based on genomic factors—may limit the use of overall survival and require the evaluation of other endpoints.

These other endpoints have included response rates, progression-free survival, and health-related quality of life, to mention a few.

There are no perfect endpoints.

We at FDA believe that the incorporation of patient-reported outcomes in product labeling is a high priority and are investing substantial resources in incorporating the patient voice in clinical drug development.

We have heard from multiple patients that response rates—that is, shrinkage of a tumor of sufficient magnitude and duration—as well as delaying the progression of a life-threatening disease is direct value to them.

Having multiple drugs available—many approved on non-survival endpoints—have transformed diseases, such as in multiple myeloma and renal cancer. These drugs can be used in combinations or sequentially after disease progression.

To have a flexible regulatory environment, changes other than a re-evaluation of endpoints is needed. Regulatory changes, such as accelerated approval, priority reviews, and breakthrough therapy designations were needed.

In oncology, we have implemented these regulatory provisions.

Approximately 50% of all breakthrough therapy designations given by FDA are in oncology, emphasizing that not only are many drugs being developed, but these future drugs may have impactful benefits to patients. Oncology-related diseases have the most breakthrough therapy designations than any other therapeutic area.

Creating a dynamic regulatory environment responsive to rapidly emerging scientific advances needs talented people. When I began at the FDA in 1999, we had approximately 12 medical oncologists. Now we have over 100.

In 1999, our oncologists were jacks of all trades without any disease specialization. Over the past decade, we have created disease-specific teams and divisions that resemble the structure of major cancer centers.

This move toward a more dynamic environment at FDA has required structural changes—namely, the creation of the Oncology Center of Excellence.

Whereas, the FDA has traditionally been orientated towards centers that focus on specific products—for example, devices, drugs, biologics—the OCE is the first center that focuses on a specific disease. The center is tasked with clinical medical oncology reviews irrespective of whether the product is a drug, device, or biological product.

The OCE—Oncology Center of Excellence—is also tasked with external outreach and academic development of our staff.

We realize that in order to be effective, we must collaborate with our stakeholders to develop discussions and conferences that will have an impact on drug regulation.

In the past year, we have had well over 30 symposiums bringing academics and key therapeutic leaders to the FDA. Many times, these conferences were conducted jointly with ASCO, AACR, ASH, patient groups, and leading cancer centers.

The OCE has in its charter to develop regulatory science in oncology. Several of our most recent initiatives include:

• Re-evaluating clinical trial eligibility criteria to ensure that patients who enter clinical trials will reflect patients who will eventually receive the approved product.
• We are interested in promoting the development of site-agnostic indications.
• We have been advocates for master protocols, umbrella protocols, and the use of common controls.
• We have worked with sponsors to use seamless design trials that eliminate the conventional division of phase 1, 2, and 3 trials that may delay drug development. We have worked with sponsors and professional groups to promote the use of these innovative designs to reduce redundancy and inefficiency of the clinical trial.
• We devoted resources to the use of real-world evidence for potential regulatory decision-making. This emerging area will in the future provide important safety and efficacy information and provide the window on how drugs are actually used.

In this short talk, I began with my reflections of oncology in the late 1970’s and what I remembered. I challenge each one of you to sit back in your chairs and ponder what oncology will look like 40 years henceforth from today.

I would like to end my talk with what I have not forgotten—and I have not forgotten the patient.

At the end of the day, patients with a life-threatening disease are more concerned about progress against the disease. They want to live longer with disease and realize this will be a result of using multiple drugs throughout their disease course. They are less concerned about what endpoint FDA uses or whether the approval was based on a single-arm study or a randomized study.

This dedication toward “progress against a disease” rather than looking at individual drug applications requires flexibility, calculated risks, and committed people to work at FDA.

2015

Remarks by Michael Taylor, 2015

It's an honor to be awarded a prize named after Harvey Washington Wiley, the man who created a "poison squad" composed of civil service volunteers who got free lodging in exchange for eating poisoned and adulterated food. I'll certainly take a close look at my lunch today.

Wiley's idea was to demonstrate that substances that were commonly used in commercial foods at the turn of the twentieth century, like borax and formaldehyde, were harmful.

Wiley had the luxury of operating in an era before IRBs, but he had to contend with another pest that afflicts today's researchers – and FDA: the press.

Wiley, chief of chemistry at the agriculture department, was greatly irritated by the media's interest in his poison squad experiments and he tried unsuccessfully to prevent newspapers from reporting on them prior to completion of his hundreds of pages long scientific manuscript. When he blocked access to the test subjects, reporters simply made up stories.

Of course, probably not even Wiley's own mother read his manuscript, but the newspaper articles caught the public's imagination. Vaudeville songs were written about Wiley and his valiant guinea pigs. About the same time, Upton Sinclair wrote a book that he hoped would persuade Americans to adopt socialism. Instead, The Jungle, along with reporting on Wiley's poison squad, persuaded Congress to pass the Pure Food and Drugs Act in 1906, creating the FDA – and Wiley was appointed to lead it.

I don't go back to Wiley's time, but I've been covering the FDA and Washington beat a long time. BioCentury has given me an opportunity to investigate and report in print on the intersections of policy, politics, science, and business for a little over 20 years. We've been doing the tv show since September 2010; it has given us a fantastic ability to communicate about topics like those that are being discussed at today's meeting to a broad audience. I spoke with another FDA hero for our very first show, Frances Kelsey, and interviewed Mary Pendergast and Bob Temple about the risk-benefit thinking involved in bringing Thalidomide back as a treatment for multiple myeloma.

I want to talk today about some of the things my colleagues and I have observed.

It is continually surprising how insulated the individuals engaged in discovering, developing, regulating and paying for new medical therapies are from each other. With a few exceptions, biotech and pharma CEOs are making decisions based on astonishingly inaccurate perceptions about FDA. Many or most people at FDA don't understand the motives, constraints, and realities of the companies they regulate. There are similar chasms of understanding when it comes to academics, payers and patient groups – and how many members of Congress have a deep understanding of the topics we're discussing at this meeting today, issues that affect the health of every American and the country's economic competitiveness?

Greater understanding among stakeholders isn't a vague or idealistic goal. The purpose is to find ways to work together to create new models of drug development. There are a large number of practical experiments being conducted today to do just that. These experiments are long overdue: innovation applied to the business and regulation of drug development has lagged far behind scientific innovation.

I'll briefly mention a few of these experiments. Many of these experiments are driven by frustration with a model that leads to what BioCentury calls the "duplication of futility" – multiple organizations working in parallel, in secrecy, often for years, only to discover that they have been traveling down a dead end. This isn't just bad for business, it is bad for patients.

Important to note that many smart people who read and watch BioCentury think these experiments are a waste of time. They may be right – they are experiments, so they might not succeed. But they have to propose something else, because today's pace – getting two or three drugs with novel mechanisms of action approved a year – isn't good enough. And it isn't good enough to say it is all FDA's fault.

The example of patients, clinicians, regulators, drug companies coming together to address the AIDS crisis shows what can be done. One result was a regulatory innovation – accelerated approval – that has literally saved and extended millions of lives. The surprising thing is that the AIDS experience hasn't been replicated.

• I-Spy 2. A trial of drug candidates in the neo-adjuvant breast cancer setting. Adaptive: researchers learn during the trial. Each woman benefits from the experience of those who went before her, and contributes to those who come next. Incorporates prospective study of biomarkers. An ongoing screening protocol. Initial test products from Abbott, Amgen and Pfizer. Will graduate to Phase III or be dropped. Can be replaced – no need to get new protocols approved, etc.

• "Open innovation" experiments. Archipelago to proof of clinical mechanism led by Aled Edwards. Patent-free development through Phase II. Directly aimed at duplication of futility issue.

• Venture philanthropy. The Kalydeco story. Patient groups driving and funding highly targeted R&D conducted by academics and industry. Keys to success: CF Foundation very actively manages R&D, doesn't simply fund it. Also created a clinical trial network and disease registry. Multiple myeloma research foundation.

• Critical Path: a huge amount of experimentation inspired by FDA's 2004 Critical Path report. Gandhi's joke about western civilization (good idea, why not try it?). Haven't delivered on the promise. Scientific opportunity, urgency and scale are the three drivers of life sciences regulatory innovation…. The science is moving fast, but in the U.S. there hasn't been urgency or scale… also a failure to make a business case and execute on it.

• IMI. Public funds matched by private in-kind investments, industry-driven translational research.

• Translational science. Low hanging fruit: There's a huge opportunity to mine FDA's data about what doesn't and won't work and disseminate that information to promote drug development. Need to get agreement to turn today's assumption that everything in drug development is secret unless there is a requirement to make it public on its head. The Critical Path Institute has taken some steps in this direction – a pilot scale. NCATS – addressing the right problems, but far from clear sufficient resources will be devoted to it, that it will be a priority after Collins leaves, or what it can contribute. Again: a business case needed.

• Emerging models for patient-driven regulation (incorporating patient perceptions of benefits and risks into decisions about endpoints, subpopulations, etc.). Areas where this could break logjams include obesity and diabetes.

• CER. Politically correct term is Patient Centered Outcomes Research. Maybe there's too much political correctness. No one could argue with the need to develop better data about what works and what doesn't work, and for who under what circumstances. But the excruciating process PCORI went through just to define its mission.. Collins threw up his hands… and its failure to clearly explain what it is going to do with

• Place where there is the least experimentation and the greatest opportunity: collaboration between payers, drug developers and academia. Merge low-cost gene sequencing data and electronic medical records. Create a system where every patient's data contributes, and where physicians can apply research at the bedside. Advances possible when clinical trial participation increases (pediatric cancer example).

There is no way to predict with certainty which, if any, of these experiments will work. But one thing can be predicted with absolute certainty: if nothing new is tried, things won't change. If you're satisfied with a 15-year and growing gap between discovery and approval of a product, ever-increasing development costs, and regulatory uncertainty chasing away investment in life sciences, that's fine. But if you think, as I do, that patients deserve better, we need even more experimentation.

After all, that's how FDA got started – with Harvey Wiley's experiments.