Remarks by Dr. Sharpless to the 2019 Biopharma Congress October 7, 2019

Speech | In Person

• Speech by: Norman E. "Ned" Sharpless, MD ; Acting Commissioner of Food and Drugs - Food and Drug Administration

Washington, DC

Good afternoon.   I’m delighted to be with all of you today for this fourth annual Biopharma Congress.

You’ve already heard from several of our distinguished center directors, as well as Dr. Scott Gottlieb.  

And you’ve also just had lunch.  So, I guess this is dessert. 

I’d like to talk today about speed of approval, and the challenges this poses for the FDA. 

I have pretty strong feelings on this topic.

In a way, it is really a question of how to maximize our productivity with limited resources.

And this topic of how to be more productive makes me think of Paul Erdos, who is my 8th favorite mathematician (I have always liked math, and I am sure you all have a list of your favorite mathematicians too).

Erdos had an interesting take on the problems of speed and productivity, although perhaps his is a cautionary tale.

He was a Hungarian number theorist who was among the most productive mathematicians of all time, working in a number of different branches of mathematics.

He achieved his productivity through an almost maniacal devotion to his field.

So devoted in fact, that he never married or settled, and lived out of a suitcase.

He would pop up on his colleagues' doorsteps without notice, saying "My brain is open," after which he would work with them on problems for a day or two before moving on.

In his later years, he used prodigious amounts of coffee and amphetamines to stay awake, working on mathematics 19 to 20 hours a day.

During his life he published more 1,500 papers, some considered true jewels of modern mathematics. 

Mathematicians even today compute their "Erdős number," a six-degrees-of-separation concept that describes how many co-authors it takes to connect you to a Paul Erdős paper.  (Think of it as Kevin Bacon for math, but involving people that are way less good looking.)

He told his friends he basically wanted to die this way: he’d give a lecture at the blackboard solving a new math problem, someone would ask him for the next implications of his proof, he’d say “I’ll leave that for the next generation”, and then he’d keel over and die.

This, by the way, is essentially what happened. (He crumpled to his death hours after providing a proof of a geometry problem during a conference in Warsaw).

Now, let me make clear that I don’t recommend adopting these methods throughout the federal government. 

There’s a lot of potential downside, but I think we can admire the passion and drive to make progress.

And we may laugh and say people aren’t really like that anymore, to which I give you Steve Rosenberg.

Steve, who is at the National Cancer Institute, is probably known to most of you as inventor of cellular immunotherapy and a cancer surgeon extraordinare.  But he has a strong sense of commitment, as well.

He has probably taken at most 40 days off from the lab in 40 years, and told me several times he planned to have his retirement party and his funeral on the same day.  

And if I might go off script for a moment, let me mention a third person who shares this maniacal devotion to great science, and who is very much in the news today:  my friend and mentor, Dr. William Kaelin.

Bill is a “real scientist’s scientist” who always insists on the highest levels of scientific rigor.

In addition to being a great researcher, he has mentored many terrific scientists who now run their own labs. 

There are many good Bill Kaelin stories, but let me tell one in some detail.

In the early 2000’s, I was a post-doc in the DePinho lab at DFCI. Our lab was right next to the Kaelin lab and we used to have joint lab meetings.

During that period, I published my first big scientific paper, in Nature magazine, about a genetically engineered mouse lacking p16, one of the most important human anti-cancer genes.

It was a big deal at the time, and I was very proud of this work (and still am).

But at almost the very same time, a post-doc in Bill’s lab, Mircea Ivan, was purifying the enzymes (came to be known as EGLN9 Prolyl-hydroxylases) that were regulated by the Von Hippel Lindau protein to hydroxylate and degrade the HIF transcription factors. 

So, almost to the week that I was feeling pretty good about my progress on understanding how cell’s evade malignant conversion, Bill and Mircea were showing us their data on how cells sense oxygen, a problem of obvious fundamental biologic importance.

And I knew my paper was pretty good.  Really good, in fact, but I also knew that this result from the Kaelin lab was historic. 

I knew it was the kind of work that would win big prizes (as it did today), and I knew it was the type of thing we’d be teaching to 8th graders some day.

Such was the pace of research on the fourth floor of the Mayer building of the DFCI back then.

I don’t personally know Gregg L. Semenza or Peter J. Ratcliffe, but I know their work well and I’m sure they are similar in their commitment to scientific rigor. 

All three are very deserving; this time, the Nobel committee got it right.

I think we can all appreciate the passion and determination of these great thinkers, and relate the work of these individuals to our own work to find solutions and cures.

And to use science and medicine to make a difference for our patients and their loved ones. 

Patients with the worst diseases often have a sense of desperation, and they expect federally funded scientists and regulators to work on their behalf with all possible speed, with the kind of singular determination I have discussed.

They are waiting and hoping for science to come up with new approaches to the conditions that affect them, and when those new ideas arrive, they want access as quickly as possible.

Patients and their loved ones are very passionate about this last point, and they will become very frustrated with anything that causes a perceived delay.

I started my career in medicine at a time when patients with end stage HIV infection or metastatic breast cancer were storming the gates of biomedical research, literally demanding access to new promising therapies for the diseases of which they were dying.

And although clinical trials are great, everybody loves clinical trials, and no doubt we could certainly do more to get patients on clinical trials in the US…

But the best way to provide this access to a new effective therapy is for the FDA to approve that therapy, as quickly as our assessment of safety and efficacy allows.

This ferocious need for progress leading to new FDA approvals is something I first experienced as an oncologist, and then really felt in a very visceral, day-to-day way as NCI Director,

And I continue to be acutely aware of these pressures in my role as Acting FDA Commissioner.

So what I’d like to talk about today is why the FDA must move as quickly as possible to provide new therapies for patients that have little hope otherwise, and how we are doing this. 

That is, how FDA is working to speed the development of new therapies for complex diseases, while always maintaining our high standards of review.

I’m sure many of you know the old line:  that there are two speeds at FDA – too fast and too slow. 

This maxim captures one of the essential quandaries of the agency:  how to balance timely patient access with our high standards for safety and effectiveness.

I would argue that one piece of evidence that we are doing a good job in this area is the fact that we are routinely, harshly criticized about this from both sides: those who say we move to quickly, and those who say we move way too slowly.  

We take this challenge seriously.  

To that end, we are constantly examining and then re-examining our practices, to make sure we are using the an ever-improving state of biomedical knowledge about a disease to clarify and streamline our process of review for the therapies intended to treat that disease.

By “re-examining our practices”, I don’t mean that we are lowering our standards.  Quite the contrary.

We apply the same legal standards for safety and efficacy to all new medicines. 

What I do mean is that our overall benefit-risk evaluation will vary depending on the circumstances and the impact of the disease, as well as our understanding of the best ways to treat that disease. 

The reason the standards exist is to make sure that approved drugs have a high chance of helping those who use them – by improving how patients feel … how they function … how well they survive.

So, naturally, we handle a treatment for something like high cholesterol differently for a diagnostic or treatment for an incurable cancer –because of what these different diagnoses mean for the patient. 

Similarly, decisions about the relative need for treatment versus the risks of that treatment are at the center point of that balance. 

For treatable conditions that have therapies available, we expect new therapies to be very safe, consistent with those already in use.

For more serious diseases with available treatments, we expect new therapies to be as or more effective than those already approved, or to decrease significant side effects compared to existing therapies.

We also know that a patient who is facing a life-threatening diagnosis will often be ready to try not just a best available treatment, but any treatment that may offer hope. 

And when no approved treatments are available, I promise you that many patients will try desperate measures, including therapies that are under development, which may have limited or no record of efficacy. 

And these such patients may not want to wait for lengthy clinical trials to be completed. 

They aren’t as worried about potential, as yet unidentified toxicities of the experimental agent. 

And they don’t want to be randomized to the placebo arm of blind trials.

Such patients can be vulnerable, and it is our job as scientists, clinicians and regulators to make sure that no one takes advantage of these populations.

Instead we want to help them get access to the most promising new therapies in a way that is safe, and if possible, within a clinical trial, where we will also learn from their outcome.

At the FDA, our approach is to continually build on an existing hierarchy by incorporating the most recent scientific advances helping to create transformational opportunities in medicine.

We work with researchers in academia and industry to strengthen that hierarchy, enhance innovation, and ensure that our regulatory decision-making is more nimble, rigorous, and effective.

To that end, we’re regularly developing and applying new ways to do our work.

For example, in the area of data science, we are making progress by harnessing real world data, employing novel analytical approaches, and linking complex, multimodal data sets in novel ways.

In this regard, I want to highlight the paper developed by Friends of Cancer Research in association with their recent Blueprint for Breakthrough Forum, “Evaluating Real-World Endpoints for an Evolving Regulatory Landscape.” 

As it demonstrates, there are real opportunities (and challenges) associated with using real-world evidence (RWE) to strengthen US healthcare.

RWE can be of significant use in many settings, including rare diseases, where more classical clinical trials data can be very hard (and expensive) to come by.

Take for example the recent use of RWE to help garner approval of a CDK4/6 inhibitor for male breast cancer. 

The drug was approved for ER+ BC in women, but clinical trials in male breast cancer have been hard (because it’s so rare). 

RWE to the rescue. I don’t think this will be the last example where RWE helps speed an approval or label expansion.

And this type of utility is one of the reasons why FDA is so committed to incorporating this important tool into our work.

We’re also continuing to promote innovative clinical trial designs:  platform trials, and basket and umbrella studies, and Bayesian adaptive trials, and pragmatic randomized controlled trials.

These novel trial designs can be very flexible and more efficient, thereby lowering costs and speeding accrual.

And of course, we want to continuously learn from every patient.

We know that patients living with a chronic disease are experts in understanding the effects of that disease and its treatments. 

Therefore, we understand, more than ever, that patients’ knowledge must inform our work in a major way.

That’s not only good science and good medicine, but also good sense.

I know first-hand just how critical it is to listen to our patients when determining the treatment most appropriate for their needs.

Beyond novel uses of data and clinical trials, I also want to focus on another important piece of FDA’s work to speed the development of new treatments.

That involves five programs established and mandated by Congress designed to expedite patient access to important medicines that fill unmet needs. 

We’re talking about treating serious or life-threatening conditions, while at the same time maintaining FDA’s bedrock standards of safety and efficacy.

These programs are Fast Track, Breakthrough Therapy, Regenerative Medicine Advanced Therapy, Priority Review, and Accelerated Approval.

Understandably, many observers often confuse and conflate these programs, but each is in fact significantly different. 

Four of the five are “designation programs” and three of these designation categories focus on a drug’s development before FDA even receives an application for approval. 

One of these designations (priority review) directly confers faster FDA review times.

The other designation programs may apply to specific types of applications, and have features to help speed review, such as rolling NDA submissions and enhanced contact with the Agency.

The fifth expedited program (accelerated approval) is pretty different.

While the designation programs rely on traditional clinical endpoints, Accelerated Approval enables an initial approval based on intermediate clinical endpoints (a.k.a. surrogate markers), and includes a requirement for further post-approval study.

But while the programs have differences, all of them – and I should point out that many products qualify for more than one – have been successful and have supported the development of important new drugs.

Of course, that doesn’t mean these programs don’t get their share of criticism.

Some of this comes from observers who believe that faster approvals mean we’re using lower standards.

Given these lower standards, they argue, some of these accelerated approvals then later wind up not working, and consequently, it is argued their development is a waste of time and money, and that these programs needlessly expose patients to ineffective therapy.

These criticisms are based on a misunderstanding of the programs and how they operate. 

To begin with, it’s important to understand that all drugs approved under an expedited program are held to the same approval standards as other FDA approvals.

For designation programs, the differences lie in the amount of time in each stage of development, as well as the extra resources the FDA commits to assist with drug development or a shortened review time once an New Drug Application (NDA) or Biological License Application (BLA) is submitted. 

As for Accelerated Approvals, these also must meet the same statutory standard for approval but may use an intermediate clinical endpoint reasonably likely to predict clinical benefit instead of a more time-consuming endpoint. 

I’ll talk a little more about that aspect in a moment.

So, our expedited approval programs allow for faster and more approvals for patients while preserving the standards of safety and efficacy. 

These pathways allow developers to take advantage of an increased scientific understanding of a disease, making it possible to develop therapies under new treatment paradigms. 

Which means more new drugs and more cures in the pipeline.

One piece of evidence:  from 1999 through 2008, just 157 drugs were approved by the FDA for orphan indications. 

Contrast that with the subsequent ten-year period, 2009-2018, when 436 such treatments were approved—nearly triple.

I would argue that this growth is evidence of an improved scientific understanding of these orphan diseases, making possible an increased use of expedited pathways. 

It also reflects the broad range of medicines being developed, and the types of diseases that are being studied.

Perhaps the brightest spot in this regard has been in the cancer space. 

When I was at NCI, I routinely would talk about how it’s a special time in cancer research.

There’s lot of reasons for that:  great new ideas like immunotherapy, cool new diagnostic technologies employing Next Generation Sequencing, great support from Congress and advocacets, all against the backdrop of a hard-won and dramatically improved understanding of the basic biology of neoplastic diseases.

That rapid progress has led to significant and sustained reductions in cancer incidence and mortality dating from the 1990’s…

With significant recent improvements in the survival of some really terrible cancers like lung cancer, breast cancer, myeloma and melanoma, and in each of these cases, I think demonstrably as a result of better therapies.

Today, the portfolio of cancer drugs, many for people lacking other options, has rapidly grown to comprise more than a third of novel drug approvals.

And when you look at it, a large fraction of these innovative new targeted therapies, immunotherapies, and other anti-cancer treatments are relying heavily on the use of FDA’s tools for expedited drug development.

This involves the changing paradigm of the benefit-risk assessment, which includes a need to reassess the endpoints for approval of transformative therapies. 

As several of my colleagues have written in The Oncologist, “although the demonstration of an improvement in overall survival remains the gold standard for drug approval, innovation in cancer research has led to use of other endpoints in regulatory decision‐making.”

These endpoints include substantially delaying tumor progression or extending progression‐free survival, or substantially reducing tumor size for a prolonged time, or improving objective response rate and duration of response, or improving cancer‐related symptoms and patient function.

All things you would want if you were a patient with advanced cancer

This understanding has reshaped how we approach oncologic drug development, and it is also having big impact beyond cancer.

It’s why FDA now tries to work with drug sponsors throughout the drug development process to tailor drug development programs to the unique context of the patient population and the disease under study.

These interactions are even more extensive when they involve breakthrough therapies and other expedited pathways.

The results are clear – more approvals of drugs that have provided meaningful treatments to patients who previously had few therapeutic options.

There’s one final point about expedited review that I want to make.

And that is that the FDA continues to evaluate the effectiveness of drugs approved under accelerated approval. 

For the product to remain on the market, there must be a demonstrated clinical benefit.

No doubt, demonstrating subsequent clinical benefit can be hard for many legitimate reasons, but it remains a requirement of accelerated approval.

And note, the FDA has not hesitated to withdraw approval or change the indication of a drug approved under accelerated approval in response to study results that do not show a clinical benefit.

For example, in 2011, after deciding there was not enough evidence to support that the drug Avastin was safe and effective for use for metastatic breast cancer, we held public hearings and ultimately withdrew approval for that indication, while leaving its other approved indications to treat other cancers.

We also moved quickly to notify the public when a larger post-marketing study of olaratumab (Lartruvo), which had been granted accelerated approval for the treatment of patients with soft tissue sarcoma, revealed that this drug did not improve survival when added to chemotherapy in soft tissue sarcoma.

The fact that this happens from time to time troubles some people, as they are unhappy these approvals ever were granted in the first place. 

I, however, would consider these examples as proof of the process.

Congress has asked the FDA to use Accelerated Approval to allow patients access to promising medicines as soon as possible, and in their wisdom, they realized that occasionally this use of surrogate endpoints would require subsequent course corrections.

That the FDA does this every once in a while, to me,  suggests this process works.

Other skeptics have argued that these types of post-market actions may have little impact on practitioners. 

That is, once we approve something for a specific indication, the horses are out of the barn.  That we’ll never be able to rein in those community doctors once something has been granted Accelerated Approval.

But research here shows otherwise. Let me give you an example.

In 2017, based on some phase 2 studies, the FDA granted accelerated approvals to 2 immunotherapies for treating bladder cancer. 

The following year, however, when data from ongoing phase 3 trials showed that an identifiable subset of these patients who received the immunotherapy had decreased survival relative to those receiving chemotherapy, the FDA decided to limit the indication for those immunotherapies to a biomarker selected patient population.

Because the decision to restrict the indication after accelerated approval based on early review of confirmatory trial data was unique, it was unclear what the impact on practitioners would be in response to such post-market safety events. 

A study by the FDA’s Oncology Center of Excellence and several other scientists in industry and academia took advantage of this opportunity to see what the effect of a label restriction was on real-world practice.

And the results of that efforts were recently published in the Journal of the American Medical Association, where the FDA scientists and colleagues found that the label changes by the FDA lead to rapid and substantial changes in oncologists’ practices, in the manner expected per the label change.

This important finding (which relied heavily on novel RWE by the way), provides another piece of evidence in favor of accelerated approval.

That is, we now know that FDA can withdraw drugs after Accelerated Approval, and also effectively restrict real world use, when needed. 

These realizations confirm the strength of the FDA’s process for ensuring safety and effectiveness of new treatments, including those receiving some form of accelerated approval.

I would close with an observation afforded me by the unique perspective I have acquired, given my time at both the NCI and the FDA.

There are still some people complaining about overly slow progress against cancer. Too expensive, too incremental, takes too long.

I do not know what science meetings these people are going to and what journals they are reading, because I don’t see our progress in cancer in that way at all.

From my vantage point, clearly cancer, and perhaps stem cell therapies and regenerative medicine, are the real bright spots of recent medical progress. 

These are areas where the FDA is seeing a really dynamic portfolio of new ideas.

Also from where I sit, I can clearly see that scientific progress across different diseases and therapeutic areas has been uneven, and it is clear that not every disease has seen as much success as these areas.

If you are not satisfied with the substantial progress against cancer mortality that we have seen, come with me to see what it going on (or not going on) in certain neuro-degenerative diseases such as Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis (ALS).

I have had the opportunity to interact with the ALS advocacy community recently, and I think it is fair to say, they are frustrated; frustrated with the lack of progress in that refractory and terrible disease.

And when I look at that problem, I see a critical issue -- perhaps THE critical issue -- a lack of basic biologic understanding of the disease.

Without biologic understanding, there are no clear targets for therapy and there are no good biomarkers for disease response.

And without good targets and biomarkers, drug discovery and development is very hard.

I see similar issues for Alzheimer’s and Parkinson’s. 

I see different but related issues for other monumental, but tough problems like anti-microbial resistance, arthritis and chronic renal disease.  

The NIH and FDA are working closely with advocates and researchers to close some of these gaps, and the FDA is working to provide additional support for sponsors seeking to develop treatments for these diseases.

ALS offers an instructive example.

There is tremendous interest from the ALS patient community, sponsors, and other stakeholders in finding new treatments, and we have been working with them to address the significant unmet need.

Recently, with their input, we finalized a well-received guidance designed to assist sponsors in the clinical development of drugs and biologics to treat ALS. 

Among the key points reflected in that guidance is the FDA’s willingness to exercise regulatory flexibility in applying the standards for approval to medical products for ALS, while preserving appropriate assurance that new therapies are safe and effective.

For instance, the final guidance includes recommendations on ways to minimize exposure to placebos and expedite clinical trials,

Approaches we endorse include the use of master protocols that can allow for the simultaneous evaluation of multiple drugs with a shared placebo group, as well as the use of adaptive trial designs and enrichment strategies.

This guidance represents an important step forward.  But we have a long way to go.

We are committed to continued engagement with the ALS community and to finding meaningful treatments for this disease…

And the same is true for any area of significant unmet need.

We have a lot of ground to cover and a lot of work before us.

But I know that with the commitment of advocates, researchers, developers, and many others, and perhaps a bit of the zeal and drive of people like Paul Erdos or Steve Rosenberg or Bill Kaelin, I am confident that we will find more therapies and cures to help more and more patients. 

I look forward to working with all of you to achieve this important goal;

Thank you.