Speech to the Research America 2017 National Health Research Forum September 7, 2017

Speech | In Person

• Speech by: Scott Gottlieb, M.D.

Remarks by Scott Gottlieb
Commissioner of Food and Drugs
Research America 2017 National Health Research Forum
Washington, DC

Last week, FDA approved the first gene therapy product in the United States. The new treatment was targeted toward a rare for of pediatric blood cancer. It will initially be indicated for only a few hundred young patients a year. But those small numbers shouldn’t taper the enormous milestone that we crossed - nor the meaningful benefit that some young and very sick patients may derive from the hopeful therapy. 

For many decades, we’ve grappled with the science to enable us to alter the gene sequences underlying disease as a way to treat human illness, using the tools of cell and gene therapy. There have been many scientific and human setbacks along the way. But the technology to do these things continued to advance, owing to the perseverance of scientists, the persistence of sponsors that were dedicated to these endeavors, and most of all, the patients who continued to brave the uncertainty of clinical trials that were the key to evaluating these new methods.

A long series of small breakthroughs consolidated into advances that enabled these new platforms, not least of which was the advent of reliable vectors to enable the safe and effective delivery of these gene products. We’ve now reached a momentous inflection point in science. FDA currently has more than 550 active investigational new drug applications related to gene therapy products, and has 76 active investigational new drug applications related to CAR-T cell products.

Gene therapy is just one of a number of new platforms that are coming to fruition as a novel means to treat disease. Two decades ago, we made some fundamental advances in life science with the firming of tools used to probe genomics and proteomics. Now, that basic science is being fully translated into therapeutic products that may radically alter the course of medicine and arrest the progress of some intractable diseases.

But a lot of our policies, and yes, our regulatory framework, are fashioned to a much different paradigm of science and drug development. So we’re challenged to adapt those policies, to make sure we have the right framework to properly evaluate the safety and effectiveness of these new technology platforms. The 21 Century Cures Act gave us certain tools and resources to address these challenges. But much work remains. Our ability to fully capitalize on new science, and maintain FDA’s gold standard for product review, means FDA also needs to modernize itself alongside the new platforms that we’re evaluating.

This modernization process has been underway for many years. It was crystalized by the Critical Path Initiative when I was last at FDA. Now we’re going to be taking some fresh steps to continue to advance similar ambitions as it relates to the development challenges associated with novel platforms. We need to make sure our policies match the complexity of the novel science that’s being harnessed to attack disease.

To accomplish this we need to ask ourselves some new questions. For one thing, how do we adjust our approach when the primary complexity and uncertainty inherent in a new product isn’t just the clinical questions related to whether it works, but the features of its delivery platform, or how it’s being manufactured?

What do we do, for example, when the most complicated risks aren’t acute toxicities that can be observed up front? Instead, they’re long term and more theoretical risks and uncertainties, such as the potential for off target effects of gene therapy interventions?

These questions challenge us to adjust our regulatory policies, and think differently about our overall mission, especially when it comes to complex products that are part of intricate delivery systems. These are situations where the products are delivered transiently, and are sometimes just a single administration. But they have sustained effects.

In these situations, determining safety and effectiveness doesn’t boil down to a judgment made at a single point in time. It’s not a binary measure – a single, discrete threshold. The proper evaluation of safety is an ongoing process. It crosses over the threshold of initial approval.

This means more emphasis needs to be placed on how new technologies perform in clinical use; during routine care. Long-term risks and benefits need to be carefully monitored. This is similar to the way that we evaluate many medical devices. Our questions related to these new platforms would increasingly relate to their long-term performance. More of our emphasis will naturally shift to our post market tools.

Over the coming months, I’m going to be talking more about some of the steps we’re taking – and steps we plan to take – to adapt our regulatory principles to the new challenges we face in properly evaluating a very different set of scientific opportunities. FDA’s goal is to make sure that our policies are as scientifically advanced as the products we’re being asked to evaluate. We need to make certain our principles for regulation allow and facilitate beneficial new innovation while making sure that FDA continues to meet its gold standard for safety and effectiveness.

Those policies will address the steps we’ll take across the entire process of clinical development. At a speech I’ll give on Monday at RAPS, I plan to talk about the steps we’re taking to make the clinical stages of development more efficient and effective. At the end of the month, I’m speaking at the National Press Club. There I plan to address how FDA approaches its broader role as a medical staff, and the post market obligations that accompany our stewardship over the evolving, and full life cycle of the products that we’re charged with regulating.

Today I want to start that conversation by talking about how FDA approaches the early, pre-clinical stages of development. I want to highlight some of the new efforts we’re undertaking as part of our overall approach to new technology and under our new “Strategic Policy Roadmap” that we’ll unveil soon, and that will outline more of our policy priorities across all aspects of our work.

For this conversation, I want to focus on the new steps we’re taking that address the pre-clinical stages of development, especially relating to new technology platforms that are becoming the defining features of profound medical advances like cell and gene therapy, regenerative medicine, and other platforms that target the molecular and genetic basis of disease.

This starts with the kinds of advice and engagement we make before new technologies are put into the traditional three phases of clinical development. It’s this early stage work that I want to focus my remarks on today. We’re taking new actions at each step in this continuum.

First, we’re adopting new policies for earlier engagement with product developers. These are especially relevant when it comes to those working in very novel areas of science. Our evidence shows that earlier and more frequent engagement can help make the initial stages of development more efficient, and increase the odds for success.

We know that academic and individual medical sponsors, as well as startups and some small-sized biotechnology companies, sometimes don’t have a full understanding of what it will take to get an IND or to get a BLA filed with FDA for their product. It’s often the smaller companies or individual researchers who are working with the most novel technology platforms. At FDA, we’re therefore encouraging very early meetings to provide early feedback to drug developers.

These efforts are a particularly prominent feature of the Office of Tissues and Advanced Therapies in our Center for Biologics Evaluation and Research (CBER). Increasingly, these meetings occur early during the period of non-clinical or pre-clinical work for an IND.

It’s been FDA’s experience that some sponsors sometimes overestimate the amount of information needed to file an IND, and that too many of the costs of development therefore get front-loaded, increasing the cost of initiating new science. Ideally, it would be easier to get products into development, with more of the costs pushed further out, after some of the initial pre-clinical work is already done, and there’s a better understanding of whether a new product has clinical promise.

Toward these goals, the FDA’s review staff is sometimes able to help significantly streamline the early development process by eliminating unnecessary pre-clinical tests or by suggesting optimal pre-clinical or clinical designs such as more adaptive trials for early stage research, or Bayesian approaches to statistical evaluation of results where randomization is not possible in early stage clinical trials.

CBER, under the leadership of Dr. Peter Marks, will be further clarifying to academic and industrial developers how we will foster the development of innovative products through the kinds of early substantive interactions that I described earlier. These new approaches to pre-clinical scientific engagement will also be featured in educational materials that we’ll be making available to sponsors. Our drug center has been implementing similar approaches to the pre-clinical process.

We’re going to be taking other new steps to make sure that our policies governing early, pre-clinical science are more closely matched to the complexion of modern technologies. One is evidenced in how clinical trials are initially designed. In certain cases, there are a lot of common features across the same platform, even as it’s used to target different genes or proteins. There may be plausible reason to recognize how a product or platform can work across multiple disease states – and leverage the learning from one setting in other opportunities. So how do we make sure we’re efficiently taking advantage of these opportunities?

For example, we may be able to take a more adaptive approach in our pre-clinical evaluation of different therapies that share a lot of common characteristics in the overall platform used to deliver a gene product. Consider two gene therapy vectors that contain CRISPR constructs differing by only one base pair. These two products might not need nearly the same amount of pre-clinical data for the second variant as was required for the first one, if we can borrow what we learn across different clinical applications of the same basic construct.

By comparison – if the CRISPR inserts were different at five or more base pairs – that might require more data. The bottom line is this:  We need to carefully but efficiently evolve our pre-clinical regulatory models to adjust to what we need as the science evolves and indicates what is critically necessary for safe application of the new technology.

These are just some of the new steps we’re taking to modernize the pre-clinical aspects of drug development. I’ll have more to say soon on these issues, as well as steps we’re taking to address the other stages of drug development. We will make sure we stay firm to FDA’s gold standard for product review, while embracing these new technology platforms.

These new platforms are the practical outgrowth of gene- and protein- based science that was firmly established just a few decades ago. They give us the potential to make a paradigmatic leap in how we approach disease and health. We are at a point in the history of medicine that is similar to other great inflections in science where fundamental principles of science and medicine became firmly established as part of a leap in public health. Our aim is to make sure our policies match the sophistication of the science we’re asked to evaluate, and help enable this new paradigm of beneficial innovation.

That’s going to be a big focus of my Medical Innovation Access Plan, and our forthcoming “Strategic Policy Roadmap.” This roadmap will serve as an organizing framework – a strategic plan for unveiling and advancing the major policy efforts we plan to undertake across all of our centers.

Today I focused on just some of the steps we are taking with respect to the pre-clinical aspects of drug review. In the coming weeks I will discuss how these same policy goals will be made evident in how we approach the clinical portion of the development process, and our life-cycle approach to medical product stewardship.

I want to thank you for the opportunity to share these ideas with you today, and I look forward to your questions.