Speech by Margaret A. Hamburg, MD
Commissioner of Food and Drugs
Stand Up to Cancer Scientific Summit 2014
January 28, 2014
Good morning. Thank you, Phil for that kind introduction. I’m delighted to be here today at this impressive scientific summit, and I am especially looking forward to a lively discussion with the distinguished panel and the audience that will follow my opening remarks.
While it is always nice to come to California at this time of the year, my decision to travel here for this meeting was an easy one – not for the sunshine and warm temperatures—but because of the important role that Stand Up to Cancer plays in the world of cancer research.
This meeting – and the work that Stand Up to Cancer does every day – exemplifies the collaborative spirit so critical to developing innovative solutions to cancer. By combining discussions of basic science with clinical and translational research in the context of ongoing projects, your work provides both a model and an opportunity for leading researchers in the field. But, just as important, it brings together representatives from industry, patient advocates, and government with the clear goal of finding new therapies and saving lives.
This approach, designed to encourage funding, accelerate innovative research, and deliver promising new treatments to the patients who need them, is a strategy very much in line with FDA’s goals and our belief in the power of what can be achieved when you bring together public and private interests in partnership for the benefit of patient care…always building on the best possible science.
And being with all of you cutting-edge experts and well-informed advocates reminds me of just how far we’ve come. To give some perspective, it was during this week in 1957, that the FDA sent to 46,000 Post Offices throughout the United States a poster warning against the Hoxsey Cancer Treatment, a worthless, fraudulent so-called treatment for “internal cancer.” As the poster noted, the FDA conducted a thorough investigation of the Hoxsey treatment and the cases which were claimed to be cured, finding not a single verifiable cure.
Perhaps most interesting is that the poster stated that “Cancer can be cured only through surgery or radiation,” and warned against “the lure of a painless cure without the use of surgery, x-ray, or radium.”
Though a minor bit of history, it does speak to some of the real progress that has been made, both in terms of elucidating the science that is involved, as well as the regulatory and other processes that help us find innovative and productive solutions using that science.
During the early years of cancer drug development, companies were looking at the blunt hammer of general cytotoxic agents, hoping they would have an impact on cancer. But of course, given their intrinsic nature, many of these agents caused very significant toxicities and side effects for patients.
Today, however, a deepening understanding of the underlying mechanisms of disease and human biology is enabling more effective approaches. Especially with new insights into genomics and the molecular pathways of cancer, we are seeing the development of exciting and promising scientific and medical advances in the form of new, targeted cancer therapies tailored to the specific characteristics and needs of patients and their disease.
More than in any other time, science today offers us extraordinary potential to transform the prevention, diagnosis and treatment of cancer—even cures – through better and more innovative therapies. Exciting new drugs that offer promise to patients—and to many who previously had no treatment options-- are being introduced and approved by the FDA with increasing regularity. Over the last several years, we have seen a significant jump in the number of drugs approved to treat cancer.
But even as we move forward along this path of medical discovery and scientific progress, charting a promising future of innovation and research, we must be realistic about the challenges before us. We must recognize that success depends on partnership—across disciplines, experience and sectors. And it depends on ensuring the right investments in science…and to my mind that means a shared commitment to regulatory science.
It may sound trite, but it is important to emphasize that important discoveries in science that can make an enduring difference for health and disease, don’t just automatically become those products that have the proven benefits, reliability, stability and quality that patients need and expect. That process involves focused attention, determination and investments in the right kind of scientific study to ensure that such translation can occur. And it means working with the FDA.
I talk a lot about regulatory science, but to my mind, it is a critical, but often underappreciated, underdeveloped and certainly underfunded component of our research enterprise. Drawing on many disciplines, regulatory science helps us develop the knowledge and tools needed to more effectively and efficiently assess safety, efficacy, quality and performance.
It enables more thoughtful, timely and successful medical product development and review. It also encourages—or should I say requires-- collaboration that can strengthen and extend our understanding of essential scientific factors in the development and progression of disease, identify treatment strategies, and offer critical insights into the potential risks and benefits of various products or treatment approaches.
Greater coordination among regulators, researchers, and industry, as well as the growing role of patients and advocates, and groups like Stand Up to Cancer, are moving us forward in powerful ways: from scientific need and opportunity spotting at the most basic level; to the design and implementation of more innovative and collaborative clinical trial designs; to enhanced sharing of research findings about what works and what doesn’t and why; to the avoidance of unnecessary duplication of effort.
In turn, this has resulted in more rapid progress from a good idea to the development of meaningful products by investigators and by industry, as has offered us new information, approaches, models and tools that can improve and streamline our regulatory systems, not just for any given product, but also across whole categories or classes of products.
All of this is part of a fundamental change in how we approach our mission of promoting and protecting the health of the public by overseeing the safety of drugs and medical devices. We are advancing a new regulatory mindset that is allowing us to move forward in ways we never could before.
It is a development that is possible largely because of advances in science and technology, but it also reflects changes in law that have given us important new responsibilities and authorities to strengthen and accelerate the regulatory process.
Perhaps nowhere is this more evident than in the way we have sought to adapt and improve models and timetables to help patients get earlier access to promising new drugs. And oncology is a particular area –though by no means the only one-- where we have seen these positive developments in the application of expedited review tools.
Consider that, over the past 3 years, FDA’s Center for Drug Evaluation and Research, known as CDER, approved 29 New Molecular Entities (NMEs) for cancer. To put that in perspective, those cancer approvals accounted for 30 percent of the novel drug approvals by CDER during the period. In contrast, cancer drugs accounted for 17 percent of the NMEs approved by CDER from the years 2001 through 2010. Moreover, nearly half of these recent cancer drug approvals (48%) are first-in-class, drugs which, for example, utilize a novel mechanism of action.
In many instances, FDA was able to speed the review of these important new cancer treatments, with 10 of the 29 recent NME approval actions taking place one month or more ahead of their scheduled PDUFA (Prescription Drug User Fee Act) date.
Nearly 70 percent of the cancer drugs approved in this recent timeframe took advantage of two or more of FDA’s expedited development programs, which include fast track, priority review, accelerated approval, and/or breakthrough therapy. The median approval time of 6 months for these cancer drugs represents a notable improvement compared to the 18-month median approval time observed for oncology drugs approved between 1992 and 1996.
The most recent, and perhaps most significant of our approaches developed to help expedite drug review and approvals is breakthrough therapy designation, which was included in the landmark Food and Drug Administration Safety and Innovation Act – or FDASIA. This approach can speed review when preliminary clinical data suggest that a new drug holds real promise of substantial improvement over available therapies.
Sponsors that receive a breakthrough designation will usually receive more intensive and earlier engagement and guidance on an efficient drug development program, as well as greater involvement by senior FDA officials.
This matters a lot, and I want to take a moment to acknowledge the amazing advocacy and support of patient groups, especially the larger-than-life leadership of Ellen Sigal, in helping to pursue and shape this important legislation.
Since that law was passed, we have already seen 37 drugs designated for consideration as breakthrough therapies, the majority of which are for cancer. Indeed, two of the first three of the designated breakthrough therapy drugs to receive approval last year are cancer drugs: Gazyva, for treating chronic lymphocityic leukemia, and Imbruvica, to treat patients with mantle cell lymphoma.
It should come as no surprise that the majority of these early breakthrough approvals were for cancer drugs, given the intellectual ferment underway in the oncology world that is paving the way for a great deal of important and innovative drug discovery and development. Indeed, this group’s work – and the emphasis you place on scientific innovation and collaboration to better serve patients – is a critical catalyst for this progress.
Of course, breakthrough is not the only means by which we are speeding up development and review of certain vital drugs. Another important way in which drugs can be approved in a more rapid, but sensible and smart fashion is under FDA’s accelerated approval program. This regulatory pathway allows the Agency to more quickly support approval of a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials.
Just a few weeks ago, for example, we used the accelerated approval process to approve a combination of two drugs Mekinist (trametinib) and Tafinlar (dabrafenib) to treat patients with advanced melanoma that cannot be removed by surgery.
These drugs were also approved using the agency’s priority review, because they demonstrated the potential to provide a significant improvement in safety or effectiveness in the treatment of a serious condition, yet another way in which we have made faster review for promising drugs possible.
It should also be noted that while Mekinist and Tafinlar are the first drugs approved for combination treatment of melanoma, each of these drugs previously was approved as single agents to treat patients with this condition, having demonstrated individual success in treating patients.
This speaks to the value of our continuing to study drugs in combination for clinical development, but also raises another important aspect of this challenge. While it was terrific that we could move forward quickly to review combination use with two already-approved drugs, we also must define new paradigms and development approaches to study novel drugs in combination. And with evolving insights into the underlying nature of the disease itself, and how our bodies and immune systems respond to and interact with the disease, it gets even more complicated.
For example, when you start looking at combinations of investigational drugs, some which target the molecular pathways of the disease, and immunotherapies, which trigger a response from the body’s immune system to fight disease, there are significant challenges, but also a great possibility. Some of the study design questions are formidable, but the combination of different drugs and different strategies into meaningful therapies for patients is enormously promising.
Certainly, the work of Stand Up to Cancer is helping to further this kind of discovery and initiative by focusing attention on and helping to finance innovative new concepts and research approaches that support some of the best science through a blend public and private resources. You are helping to break some of the conventional barriers of drug development and forge new ways to promote breakthroughs. We are excited about these kinds of approaches and believe that there is a lot more that can and must be done…together.
Let me mention one example of a recently initiated partnership FDA is involved in that I think will be extremely valuable. Through a strong collaborative effort between FDA, Friends of Cancer Research, the drug industry, Brookings Institution, and a number of other groups, we developed what is called the Lung Cancer Master Protocol. It is an entirely new approach that takes advantage of our growing engagement in personalized medicine.
The effort involves a clinical trial design and infrastructure that will provide for multi-drug, multi-arm, multi-site trials, in which the same patient population will be screened for multiple genetic traits at the same time. It is a highly efficient design that will allow several therapies specifically targeted to individuals with particular genetic characteristics.
I’m proud that FDA has played a key role from the beginning, but it is the partnerships that are really so significant And there are, of course, other examples of innovative protocols that involve wide ranging collaborations…some that you know well.
These approaches are important, not just because of the results they deliver for the disease and treatments under study, but because they can be adapted or extended to other areas of research and to other diseases. In this way they provide a model for future collaboration between FDA, academic researchers, industry, and, most importantly, patients.
So I look forward to working together with you to develop other models and ways of thinking—drawing on cutting-edge science and our most expert and creative scientists – to help us pursue improved strategies for drug development and review. I think we all share the sense of opportunity—and obligation—to deliver what science offers and what patients need. And your work and your voice are critical to this effort.
And now I want to enlist your additional help. I can assure you that at the FDA, we are deeply committed to the proposition that we must do all that we can to streamline and speed the regulatory process for the benefit of patients, particularly for serious or rare conditions, but this approach is not without its critics.
A recent springboard for this discussion came with an article published in the current Journal of the American Medical Association, based on a study by several Yale School of Medicine researchers. The analysis examined FDA approvals of “novel Therapeutic Agents” from 2005-2012 and concludes that the ways in which we arrived at those approvals “vary widely in their thoroughness.” Or, in the words of one study author, “Not all FDA approvals are created equally.”
More specifically, the authors found that many of the new drugs we review require a demonstration of efficacy through large randomized controlled trials, others won approval on the basis of a single clinical trial, and still others involved only small groups of patients for shorter durations. They also pointed out that about 40 percent of approvals included trials in which the new drug was compared with existing drugs on the market.
Although I don’t think it was actually the authors’ intent, a number of media reports and commentators framed this as a criticism. But frankly, I would be more troubled if we used a rigid “one size fits all” approach.
Such criticism goes directly to FDA’s ability and mandate for flexibility in tailoring clinical trial requirements for each drug and the disease area in which it is being studied. But it should be underscored that no matter what type of trial is applied, the Agency always applies the same statutory approval standards of safety and efficacy to all drugs in order to be marketed in the United States.
Increased flexibility does not mean abandoning standards…and it certainly does not mean abandoning science. Just the opposite. We need to employ the best science in ways that will increase our efficiency, productivity, and our shared ability to find creative solutions to the challenges that confront us.
Another factor to consider is that FDA has a robust program for postmarket surveillance to help ensure the benefits of marketed drugs continue to outweigh their risks. Prescribing information and patient medication guides supplement this process with important information on safety and efficacy that patients and health care professionals can use. Furthermore, should significant safety issues arise, we work quickly and transparently to take appropriate actions, whether a request for additional study, possibly a recall or limit on use, or an alert to patients and health care providers so they can make informed decisions about treatment.
As regulators, it is our duty to provide oversight these drugs, both before and after approval. This requires continuous monitoring, assessment, and balancing of risks and benefits. There will of course be differences among groups as to what constitutes an acceptable risk, and frankly there are not always clear or absolute answers.
As you well know from medical research—if not from –life -- we often must deal with uncertainties and unknowns. Taking on a certain level of risk is an intangible component of such a regulatory process.
Implicit in this challenge is the recognition that there is a need to balance our eagerness to find ways to address the needs of patients for the most serious illnesses by responding as quickly as possible to develop treatments, with the need to ensure that the benefits outweigh the risks.
Increasingly, in cancer research we have evolved from the view that we must protect patients from the consequences of research, to a view that we must protect patients through research, in order to assure their access to new and effective medications.
Our responsibility to help translate the newest discoveries and research into treatments for patients who are critically in need is precisely the goal of drugs developed through an expedited approval process. As with all drugs, adverse effects may become apparent only after a drug is marketed and used more widely.
In fact, it would be remarkable if some of the drugs that receive expedited approval did not have their usage indications modified in some way, including possibly coming off the market either temporarily or permanently, as a result of new information and continuing study. It is disappointing when that happens, but it is not a failure of the system or approach. In fact, it is the reverse. Balancing that risk with the potential benefits of getting promising drugs to sick patients with limited options must continue to be our point of reference … and action.
Building on that thought, and as I come to a close in my formal remarks, I would briefly draw attention to the title of this session, “Managing and Overcoming Roadblocks in Drug Development and Approval.” To me, this seems unnecessarily negative. One person’s roadblock is another person’s protection or solution. One person’s approach to drug approval is too fast, while others would say it is too slow. I prefer to think of FDA’s role as a gateway or bridge to innovation, not a roadblock.
But, in fact, we are all in this together…and we need your support as we seek to find new and better ways to do our job. On the science side, FDA can ask for certain studies and we can encourage the collection of certain kinds of data in certain ways. And, of course, we can say “yes” or “no.” Yet the truth is that the better the science, the easier our job. We don’t have to agonize over the data and statistical analyses. The answers are obvious.
It is clear that our ability to meaningfully streamline and modernize our regulatory pathways -- to best leverage the opportunities in science today, and most importantly, to address the serious and pressing unmet medical needs before us -- will depend on the development of the necessary scientific knowledge, tools and approaches. It will require new paradigms and models … and it will require new ways of doing business -- it cannot be business as usual. It will also require taking some risks.
This group is unusually qualified to support these important transformations and to send the message that we have real opportunities for innovation in the treatment of cancer. Our shared goal is to expand treatments, make available new drugs, and, hopefully, develop new cures and strategies for prevention.
Our shared success will depend on innovative strategies, true partnerships and a commitment to understanding the science that underlies our efforts. Stand Up To Cancer embodies this vision and your work has moved us all closer to our goals. It is an honor and a privilege to be with you this morning and as we look to the future, I am excited about the possibilities of what we can accomplish together.