- Speech by
Scott Gottlieb, M.D.
Commissioner of Food and Drugs - Food and Drug Administration ( May 2017 - April 2019 )
Remarks by Scott Gottlieb, MD
Commissioner of Food and Drugs
2018 Community Oncology Conference
National Harbor, MD
(Remarks as prepared for delivery)
The treatise on the history of cancer, The Emperor of all Maladies, recounts the work of Burt Vogelstein in the late 1980s, who described the genetic changes required to initiate cancer. Vogelstein had found a strikingly consistent pattern between transitions in the clinical stages of cancer and certain genetic features of the disease. It was a major discovery -- but one that, today, seems almost rudimentary and second nature.
It turned out that cancer cells didn’t activate or inactivate genes at random. Instead, the shift from a premalignant to an invasive and eventually a metastatic form of cancer correlated precisely with the activation and inactivation of specific genes. This process unfolded in a strict and stereotypical sequence.
Vogelstein’s finding would provide the basis for the notion of the somatic evolution of cancer. And in the years going forth, cancer biologists would begin to more carefully measure the functions of these mutations. In the span of just a decade, the basis for diagnosing and treating cancer would be transformed.
Among many other modern applications, Vogelstein’s pioneering ideas that somatic mutations represent uniquely specific biomarkers for cancer created the field now called liquid biopsies.
This discovery gave rise to new medical advances that are unfolding so quickly that it presents challenges in the development, evaluation, and adoption of the new treatments that are derived from this innovation. But these technologies also present many transformational opportunities.
There’s an increasingly close connection between the identification of genetic changes that give rise to cancer and drive its advance, the development of drugs targeted to these genomic features, and the use of these same tools to diagnose disease and select the right treatment for the right patients.
When it comes to complex, serious, and life-threatening diseases like cancer, promoting and protecting public health requires the FDA to adopt policies to ensure that regulation serves as a bridge to this oncology innovation, and not a barrier to it.
The application of Vogelstein’s original work to the development of modern diagnostic platforms that can advance drug development and improve the delivery of patient care is just such an innovation. And the advent of next generation sequencing is one such expression of these new advances.
NGS platforms are diagnostic technologies that are capable of processing multiple DNA sequences in parallel. They’re being used to match treatments to patients to improve outcomes, and also to help improve the development of new drugs. And I want to talk today about some of the new steps we’re taking at the FDA to secure these new opportunities for patients.
The rapidly falling cost of NGS sequencing is expanding its role in routine treatment decisions by allowing analysis of whole genomes of matched normal and tumor cells to identify potentially actionable mutations, including rare variants and tumor sub-clones. The same tools provide the way to target cancer with precision guided treatments or better direct patients toward clinical trials for testing promising compounds.
The FDA recognizes the tremendous potential of NGS technology to guide and improve patient outcomes. And we’re developing a policy approach to keep pace with fast-moving NGS technologies that give patients and clinicians confidence in these panels' analytical and clinical validity, while still allowing these sequencing systems to be efficiently updated as new genes, or gene variants, or improved algorithms come online.
Often this means comparing NGS panels to other approved genetic tests with well-known performance characteristics, to validate the performance of the NGS panels.
To date, the FDA has authorized three NGS onco-panels that can screen hundreds of oncogenes and thousands of variants.
These panels can accelerate cancer drug development and improve clinical outcomes by reducing patient screening time and costs. These technologies can help reduce the risks associated with the need for multiple tissue biopsies. And these platforms can be rapidly updated to detect new oncogenes or gene variants as these markers are identified by researchers.
As FDA-approved NGS tests are used in clinical settings, it makes it easier, and less expensive, to screen patients for tumor mutations with a single test, and then efficiently match them with available clinical trials. That enables more effective drug development, and allows drugs to be targeted at biomarkers found across multiple tumor types – like tumors that are microsatellite instability-high and therefore likely to benefit from treatment with selected checkpoint inhibitors.
The FDA is working diligently to ensure that our regulations are as nimble and sophisticated as the science driving these technologies so that clinicians and patients have access to them as soon as possible while still providing patients with the reasonable assurance of safety and effectiveness they expect.
But there’s nothing inevitable about the progress we’re seeing today; nothing that assures us that future progress can’t be delayed or derailed. Today’s success is the result of decades of bipartisan policy consensus, beginning with Nixon’s War on Cancer; five reauthorizations of the Prescription Drug User Fee Act since 1992; strong intellectual property protections that encourage capital investment in new innovation; investments in the National Institutes of Health, in visionary legislation like the 21st Century Cures Act; and, not least, in the determined and vocal patient advocates holding policymakers, industry, and regulators accountable for continued progress in the fight against cancer.
That’s a recipe for world-leading oncology innovation. So, it’s no surprise that the world’s most innovative cancer therapies were either researched and developed in the United States, or were developed elsewhere but launched in America.
But America’s innovation ecosystem depends, above all, on public confidence in the institutions and rules that support it.
Erode that confidence, and the bipartisan consensus supporting innovation we’ve seen for the last 40 years will splinter.
If oncology is at the leading edge of precision medicine, it’s also where we see some of the biggest stressors threatening the foundations of continued success. This is especially true when it comes to the public’s belief that innovation is sustainable and accessible for all cancer patients. There are a number of challenges. But I want to spend some time on a few of them.
The first is costs. Drug treatment costs are only a fraction of total care oncology costs, but cancer patients are disproportionately shouldering the cost of oncology medicines.
Rising co-pays and co-insurance are pushing far too many patients into a financial no-man’s land where sometimes they must literally choose between exhausting their bank accounts, or going without access to potentially effective treatments.
I don’t think that any patient should be penalized for their biology. The true purpose of insurance is to shelter patients from financial ruin in the event of a catastrophic illness.
And a cancer diagnosis is the definition of a catastrophic illness.
But the perverse reality of the market today is that cancer treatment comes with its own financial toxicity.
The FDA is taking an interest in this problem because, although we don’t regulate drug prices, if anticompetitive forces and profit taking across the drug supply chain are pushing effective treatments out of the reach of patients, the full benefits of innovation to improve public health are not being realized.
And although it isn’t our primary role, Congress gives us responsibility for fostering competition in product markets.
We’re committed to promoting competition using the tools at our disposal to make more affordable generic and biosimilar options available to patients, and to reduce anticompetitive behavior that can unfairly delay access to those products. We’ll have much more to say about some of the additional steps we’ll be taking; including a plan to foster more development and competition when it comes to biosimilar drugs.
The second issue is development costs and timelines. This is where new technologies like NGS come more sharply into play.
With a few notable exceptions, drug development costs are still soaring; too many trials still fail, often in late stages, not just because the science is challenging, but also because the clinical trial paradigm is badly in need of modernization.
That includes oncology.
We need new approaches that can help improve trial productivity, and enable more efficient clinical trial designs like master protocol trials, while also ensuring that the results of those trials are more applicable in real world settings.
That’s important because poor productivity is driving at least some of our drug pricing conundrums.
Drug pricing reflects the cost of capital required to undertake the direct and indirect costs of discovery and development. These aren’t just the direct cost of the trials, but also the financial cost of the time and risk intrinsic in these endeavors.
These high development costs ultimately translate into higher prices, because the expected returns on a new drug development program must be pushed higher to justify the high cost of the capital to undertake these endeavors. But if we can reduce not only the direct costs of development, but the time and risk embedded in these endeavors, we can reduce the cost of the capital needed to underwrite new discovery. We can have more capital chasing more opportunities to improve patient care. And we can do it all and lower costs for patients.
A more productive industry will be able to deliver greater gains in less time to cancer patients, while supporting lower pricing.
And so we must continue to take steps that can help make the delivery of treatments more efficient and effective, and also reduce the cost of developing these innovations.
Some technologies lend themselves to achieving both of these goals. You can have greater certainty around benefit and risk, and also faster development programs that cost less to run. And in doing this, you can achieve better care for patients.
Modern diagnostic tools like NGS is one such advance. And that’s one reason why we’re taking new steps to help advance these technologies, and better adapt them to patient care.
Today, we’re releasing three new FDA Guidances on NGS and in vitro diagnostic development. I believe these new policies will encourage further development of these powerful diagnostic platforms by enabling more efficient regulatory review.
By clarifying efficient pathways and transparent standards for the review of NGS systems, sponsors will have greater incentives to bring more diagnostic tests forward for regulatory review and encourage data sharing to support rapid development of drug and diagnostic treatment systems.
As I noted earlier, we’ve seen that biomarker-guided oncology trials are more likely to succeed, and are more likely to demonstrate impressive patient outcomes in early stage trials.
This includes tissue-agnostic therapies where the treatment targets a common biomarker across multiple tumor types – like mismatch repair deficient solid tumors (dMMR) - rather than the location in the body where the cancer originates.
The FDA’s vision is that NGS-based tests can be developed, validated, and offered for clinical use through a process that leverages appropriate standards for analytical validity – which is a measure of the test’s expected performance characteristics – along with methods for assuring quality systems controls, and community assessment of a test’s clinical validity. This combined approach can simplify the premarket review process.
The first guidance we’re releasing today, "Considerations for Design, Development, and Analytical Validation of NGS-Based In Vitro Diagnostics Intended to Aid in the Diagnosis of Suspected Germline Diseases," discusses the FDA’s considerations for analytical validation of next generation sequencing-based tests that are intended to help diagnose suspected germline diseases.
For oncology, germline cancer predisposition contributes to about 5 to 10% of observed cancers. For cancer predisposition syndromes, such as Lynch Syndrome, interventions like colonoscopies may be able to improve expected survival by sharply decreasing the rates of colorectal cancer.
The FDA believes that the analytical validation recommendations laid out in this guidance could spur the creation of consensus standards for NGS-based tests that will be developed by the community and potentially recognized by the FDA.
We also believe that it may be possible for NGS tests for germline diseases to be classified as moderate risk (class II) and potentially for the FDA to propose exemption from premarket review based in part on conformance to the recommendations in this guidance or to standards that address these recommendations.
The second final guidance, "Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics," describes the FDA’s considerations for recognizing publicly accessible genetic variant databases as sources of valid scientific evidence to support clinical validity during premarket review.
One potential example of such a consensus database would be the NIH’s ClinGen database. This database works to standardize the clinical annotation and interpretation of genomic variants through evidence-based expert consensus.
FDA-recognized databases can support sponsors’ assertions about the meaning and clinical significance of germline or somatic mutations, rather than requiring the test developer to generate their own evidence for each variant.
This guidance also outlines how database administrators can voluntarily apply to the FDA for recognition.
Eventually, we believe that this guidance will encourage expert-based crowd sourcing of NGS evidence generation, curating, and data sharing – which can all advance the development of high quality precision medicine treatments and diagnostics.
Finally, we’re issuing a draft guidance, "Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination," which describes for sponsors of certain oncology trials an optional streamlined submission process related to determining whether use of an investigational in vitro diagnostic (IVD) -- including IVDs that incorporate NGS technology -- in a trial of investigational cancer drug or biological products is considered significant risk, nonsignificant risk, or exempt from review. This is a step toward our goal of having a common filing for a drug and diagnostic system where the drug is co-developed with a diagnostic test.
Significant risks can occur if the test would, for example, cause a patient to be assigned to an experimental treatment and forgo highly effective treatments that are already available. One example is for first-line treatment of Hodgkin’s Lymphoma, or early stage estrogen-positive breast cancer.
This guidance reduces burdens on sponsors and on FDA staff by outlining circumstances under which sponsors may be able to include information about an investigational IVD into the Investigational New Drug (IND) application submission to the FDA center responsible for the therapeutic product – in this case either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER).
CDER or CBER would then coordinate with the FDA’s Center for Devices and Radiological Health to determine whether use of the investigational IVD in the trial is considered significant risk, non-significant risk, or exempt from further pre-market review.
In this case, NGS test developers and drug sponsors could engage with a single agency lead during the submission of INDs. They’ll be a clear line of communication between reviewers and sponsors, and on a single timeline. It will avoid the potential for confusion that could come when NGS and drug sponsors engage separately with different medical product centers.
The policy approach outlined in these new guidance documents will provide test developers with a more efficient path to market. These new policies will improve the FDA’s ability to protect public health by ensuring these tests provide accurate and meaningful results, while at the same time speeding patient access to NGS assays by lowering barriers to innovation.
Taken together, these guidances pave the way for possible down classification and even exemption from premarket review of NGS-based tests that demonstrate conformity with future FDA-recognized standards and tests that rely on demonstrating their validity against FDA-recognized databases.
Most importantly, it will give patients, payers, researchers, and clinicians greater confidence that NGS platforms can be used to inform treatment decisions and improve patient outcomes.
The actions we’re taking today will encourage greater innovation and accelerate the adoption of tools that can increase the productivity of clinical research and improve the delivery of cancer care. It will help unlock the promise of the findings first made three decades ago by Vogelstein and others.
We talked longingly about the era of truly personalized patient care for many years. When it comes to oncology, that promise is not just being made manifest. It’s becoming the clinical norm.
Patients should expect treatments and approaches to care that are more targeted, more successful, and more cost effective.
Payers should be able to demand higher value solutions that get the right treatment to the right patient at the right time.
And doctors should have the tools they need, whether they are practicing in an academic or a community setting, to more seamlessly carve these approaches into their clinical practice.
We need to make sure that these technologies are available across the continuum of medical practices. The steps we’re taking at the FDA to lower the cost of developing these tools should also help make the most promising medical opportunities more ubiquitous and more egalitarian.
These are the opportunities we should demand as doctors and patients. And along with these new innovations, we should also expect to make continued gains in the effort to reduce the death and suffering from cancer.
In a very short period, we’ve transformed the treatment of cancer. It’s true that these advances have come at an economic cost. But the technology is at hand to make drug development and patient care far more efficient, cost effective, and efficacious. We strive for all these things. And we should settle for nothing less.