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Implementing the 21st Century Cures Act: An Update from FDA and NIH - Oral Statement

Oral Statement of Scott Gottlieb, M.D. Commissioner, Food and Drug Administration, Department of Health and Human Services
Before the Subcommittee On Health, House Energy And Commerce Committee, U.S. House Of Representatives

July 25, 2018

Chairman Burgess, Ranking Member Green, and Members of the Subcommittee:

I want to thank you for the opportunity to testify today on FDA’s implementation of the 21st Century Cures Act.

Almost two years ago, many of the members of this committee hailed passage of Cures as a potential game-changer for patients.

I agree.

And at FDA, we’re working with industry, providers, patients, and many others to turn that bipartisan vision into reality. 

I’ve provided a comprehensive list of our Cures activities in my written statement. But I’d like to focus my brief remarks on one cross-cutting priority under Cures:

Modernizing clinical trials. 

FDA has embraced innovative and efficient trial designs and novel endpoints, including surrogate endpoints, that enable the more agile and patient-centered clinical trials envisioned by the Cures Act.

And we’re not doing it alone. 

We’ve embraced the spirit of collaboration in Cures and are working with our public and private sector partners to better meet shared public health goals and address cross-cutting scientific and technical challenges.   

For instance, the Center for Devices and Radiological Health (CDRH) is working the Medical Device Innovation Consortium (MDIC), a public–private partnership among federal agencies, industry, nonprofits, and patient organizations -- to facilitate computer modeling and simulation as a validated and accepted part of clinical trials.

MDIC members have volunteered their expertise and experience to create a framework to augment clinical trial design with “virtual patients” by leveraging the FDA’s Guidance for use of Bayesian statistics in medical device clinical trials.

Virtual patients use predictive modeling, including evidence from prior clinical trials, human anatomy, physiology, and disease progression to predict the potential safety and efficacy of novel medical devices in computer simulations.

Today, the MDIC working group is conducting a mock submission, demonstrating how to implement virtual patients in a prototype trial design and device submission.

If it can be shown that virtual patients are similar, in a precisely defined way, to real patients, future trials may be able to rely partially on virtual-patient information, when appropriate, thus lessening the burden of enrolling additional real patients.

High quality registries, created by sponsors, health systems, or patient organizations, also have the potential to play a critical role in device-approval decisions as a source of evidence from clinical experience (“real-world” clinical data).

Along with electronic health records, registries hold enormous potential to efficiently answer important premarket and postmarket questions.

For example, registry data have been used as historical controls in premarket studies and allowed sponsors to meet postmarket data collection requirements in less time and at lower cost.
These tools will enhance efficient evidence generation and analysis across different medical products and across the agency.

Our aim is simple: innovative, advanced evidence generation to assure the timely availability of safe and effective therapies.

More and more, we have the tools to make sure the right drug or device reaches the right patient at the right time. This long-sought vision for medical care is achievable. We can help more patients avoid treatments that are likely to be ineffective or toxic. 

The Cures Act is catalyzing these approaches, and catalyzing the development of new precision medical technologies that are enabling us to target, arrest, and cure intractable conditions.

These advances aren’t cheap. Access and cost is an issue.

And I know that some question whether our market-based system for medical innovation is financially sustainable. 

They ask if we can afford this coming wave of precision-guided therapies. I’d say we couldn’t sustain our system without them.

New advances like regenerative medicine and gene therapy can displace costs associated with serious chronic illnesses, and rare disease, by restoring function and reducing reliance on costly medical care delivered in hospitals and nursing homes.

The best solution isn’t to reduce market incentives for innovation, but to create more efficient clinical development and execution for generating the evidence that we need to support safety and efficacy -- all without compromising the FDA’s rigorous gold standard for product regulation.

That brings me back to modernizing clinical trials.

The current one drug, one trial process can be wasteful and inefficient. It can delay both access to innovative therapies and developing sufficient evidence about their performance.

It doesn’t leverage the clinical trials that we have underway.

Approaches like basket trials, master protocols, and seamless trial designs allow us to learn more about new drugs, and even evaluate different drugs in the conduct of the same clinical trial.

Rising trial costs and complexity undoubtedly impacts market competition and drug pricing. And it can be a barrier to getting timely competition to newly approved branded innovator drugs.

One reason we may be seeing higher costs is because it takes longer for competition to reach the market in some of these drug categories where you have specialty drugs that are targeting unmet medical needs. And when competition does eventually emerge, it’s taking many more years to finally reach patients.

We studied this question. And the data confirms these trends.

A new FDA study considers the number of drugs or biologics that CDER has approved in the same class. They’re drugs that use the same mechanism to produce a physiological change in the same or related condition. 

We found that new competition isn’t entering the market as quickly for these drugs. In other words, when a novel sole source drug wins approval it faces no competition from other drugs in the same class. Follow-on drugs and biologics to compete with the first in class have been arriving more slowly. 

Here are some results from the data we looked. We plan to publish the full analysis soon.

For non-orphan pharmaceuticals, which treat conditions affecting larger patient populations, 41 percent of the first-in-class approved between the years of 1991 and 2000 had at least one competitor in the same class within five years. 

This rate dropped sharply over the next decade.

For the years from 2001 to 2010, for the same kind of cohort of medicines -- first-in-class products that were approved to treat patients with prevalent conditions -- only 18 percent of these drugs had a within-class competitor after five years.

Another way of interpreting the data is to describe the lag in any competition.  For the older classes, where the first in class was approved in 1991 to 2000, nearly a quarter had a competitor within two years.  For the cohort where the first-in-class was approved in 2001 to 2010, it took an additional five years for there to be nearly as much competition. By year seven, competition still lagged the previous cohort, with only 22 percent of classes having any competitor.

We see similar patterns in most rare disease treatments.

Consider first in class orphan drugs and biologics for non-cancer indications. For drugs approved between 1991 and 2000, 26 percent had at least a competitor within five years. The comparable rate for the 2001 to 2010 cohort was 13 percent.

These trends mean that costlier, branded drugs may enjoy longer periods without facing competition from products in the same class. This may increase their pricing power.

For orphan drugs, where conducting trials can be hard, these periods can extend long after patents and other exclusivities lapse.

We need to understand why. Part of it has to do with the difficulty of running clinical trials with a second to market drug, especially after there’s available therapy for an unmet need. It’s becoming harder and harder to be second. That’s a problem.

Efficient, modern approaches to designing and conducting clinical trials can address some of these challenges.

These approaches also advance the spirit and letter of Cures.

These approaches allow us to learn more about the safety and benefits of new drugs, more efficiently. It gets back to my point that you can have greater efficiency, and a greater assurance of FDA’s gold standard, at the same time. If what you’re doing is modern, evidence-based, and rigorous.

To advance these and complementary goals, the FDA is pioneering a number of critical advance in clinical trial design.

First are Master Clinical Trial Protocols. These include basket, umbrella, and platform trials. These approaches can sharply increase trial efficiency and lower costs. They move away from one-drug, one-disease trials, and allow the testing of multiple drugs against one or more diseases or disease subtypes based on biomarkers using a common clinical trial infrastructure. 

Platform designs like I-Spy 2 for metastatic breast cancer, GBM AGILE for glioblastoma, and DIAN-TU for Alzheimer’s are the trial equivalent of a hub and spoke airport.

These approaches that were first pioneered in oncology are now being used more widely across FDA, in other therapeutic areas.

They can, when appropriate, use a common comparator arm, a strategy we encourage. And they can also use adaptive algorithms to match patients with treatments that are more likely to be successful in their disease.

Another approach is seamless trial designs that compress the traditional three phases of trials into one continuous trial.

Through these approaches, you run one continuous trial. And as you enroll new patients, you expand subsequent cohorts of enrolled patients using the information you learn about the features that help predict benefit from a new treatment.

We’re going to be publishing a guidance soon that lays out how product developers can conduct these seamless trials; how to expand cohorts as trials progress; and the clinical criteria that can be used to expand cohorts as the trial advances.

A lot of the time and cost of clinical development is spent waiting in between the starting and stopping of the traditional three phases of trials. The clinical trial infrastructure profits from this starting and stopping. I know contract research organizations have built elaborate business models around this approach. But patients aren’t always benefiting from these approaches. If there are more efficient ways to generate better evidence, these are the kinds of reforms we want to advance.

That new guidance will provide advice regarding the design and conduct of first-in-human clinical trials with multiple expansion cohorts intended to efficiently expedite the clinical development of cancer drugs. These are trials where patients are often selected based on biomarkers, and where the science tells us that we may be able to more easily demonstrate a robust impact on intermediate clinical endpoints or surrogate endpoints that are likely to correlate with long-term clinical outcomes.

We’ve already successfully used these approaches with some of the new immunotherapies. The guidance will lay out the design of these seamless trials, and how they can be best applied.

In such an approach, each cohort is designed to answer a specific question about the safety and efficacy of the drug. Such an approach lets you ask more questions, and get more answers.

For drugs that might already qualify for breakthrough therapy designation, expansion cohorts can be used to quickly expand enrollment in biomarker selected Phase 1 cohorts, and evaluate the drug in one seamless – continuous -- clinical trial.

Multiple, concurrently accruing and individual cohorts can allow us to better assess a lot of information in one large trial, answering questions about safety, the pharmacokinetics related to how a drug is absorbed and distributed in the body, and anti-tumor activity. These questions can be evaluated in cohorts that are specially designed to assess these different, important questions. With more efficient development using a seamless design, the whole trial can be completed with a few hundred patients.

These approaches have been used for novel first-to-market drugs. They can also advance second-to-market competition.

Another tool we’re using to modernize clinical trials are surrogate endpoints. These may be relevant when clinical outcomes might take a very long time to study. Or when the clinical benefit of improving the surrogate, such as controlling blood pressure or reducing HIV viral load, is well understood.

In the cancer space, advances in science are facilitating development of oncology products using innovative endpoints for both accelerated and traditional approvals.

For example, minimal residual disease response rate has been used as a surrogate endpoint for accelerated approval for therapy in acute lymphoblastic leukemia. And metastasis-free survival has been used as a clinical endpoint for traditional approval for therapy in non-metastatic castration-resistant prostate cancer. 

The use of surrogates for cancer can put promising treatments into the hands of high-risk patients years before they would’ve been available using previous endpoints, and, in some cases, increase the likelihood of a achieving a long-term remission.
To advance this science, today we’re meeting one of our commitments under the Cures Act related to surrogates.

The Cures Act mandates that the FDA publish a list of surrogate endpoints which were “the basis of approval or licensure (as applicable) of a drug or biological product” under both accelerated and traditional approval provisions.

The Surrogate Endpoint Table we’re publishing today fulfills this requirement. It will provide valuable information for drug developers on endpoints that may be considered and discussed with FDA for individual development programs.

When I first came to FDA in 2003, HER2 positive metastatic breast cancer was one of the most dreaded cancer diagnoses.

Immuno-oncology was considered a dead end.

Gene therapy was on hold. And gene editing was nowhere.

Patients with recalcitrant leukemias and lymphomas were often very tragically forced to measure their lives in months.

Patients with Hepatis C were still being treated with ribavirin and interferon -- toxic drugs that were poorly tolerated.

And we didn’t cure many of these patients.

Parents of children with Type 2 diabetes had to wake them up every few hours at night to check their blood sugar and possibly administer insulin.

And we didn’t have the concept of digital health, because smartphones, large libraries of apps, didn’t exist, and artificial intelligence for medical applications was still in its infancy.

What a difference just fifteen years makes.

Checkpoint inhibitors are producing unprecedented outcomes for some patients with metastatic melanoma and lung cancer.

The cure rate for Hep C is at 95 percent or better, thanks to far more effective, and far less toxic treatments.

Genetically engineered T-cells have demonstrated durable remissions in up to 60 percent of patients in clinical trials with certain deadly, drug resistant leukemias and lymphomas. 

CLL and CML are now often managed as chronic illnesses.

Many patients with these blood cancers can maintain stable disease for years, or even decades.

Multiple new lines of therapy exist for HER2+ metastatic breast cancer. The adoption of new endpoints, combined with surgery, has widened the number of effective treatment options for these patients and reduced the risk of disease recurrence.   

Pediatric patients with Type 1 diabetes now have access to an FDA-approved closed loop insulin delivery system that uses an algorithm to self-adjust the delivery of basal, or background, insulin every five minutes based on real-time data gathered from the sensor, reducing or even eliminating the need for disruptions in sleep caused by frequent blood glucose checks.

And the FDA has approved medical apps that use smartphones or tablets to scan a patient’s eye for signs of macular degeneration and transmit the results to a provider; along with clinical decision support systems based on artificial intelligence that help providers evaluate potential stroke patients or lung and liver cancer lesions with greater confidence than they can without the software..    
Many of these approaches reached patients faster because the FDA embraced the imperative of modernizing clinical trials.

It’s an effort that we are expanding thanks to the Cures Act.

Every American has already, or will one day, face a serious medical diagnosis, either personally or through a loved one.

We need to reduce the burden and cost of advancing care. And we need to make it easier for competition to reach the market once we have a breakthrough, so more people can access it.

The clinical trial reforms we’re making today will help ensure that more patients who find themselves in these hard circumstances have a better chance of a finding a cure. And that market competition helps to keep those options affordable.

Thank you. 

Page Last Updated: 07/25/2018
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