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  1. Speeches by FDA Officials

Speech

Event Title
Remarks to the Friends of Cancer Research 2018 annual meeting
November 13, 2018

Speech by
Anna Abram
Leadership Role
Deputy Commissioner for Policy, Legislation, and International Affairs - Food and Drug Administration

Remarks by Anna Abram
Deputy Commissioner for Policy, Planning, Legislation and Analysis
Friends of Cancer Research Annual Meeting 2018
Washington, DC

Remarks as prepared for delivery

Thank you for that kind introduction.  FDA has enjoyed a long and important collaboration with your organization. Thanks to your leadership, an important expedited development program was added to the FDA’s toolkit, the Breakthrough Therapy Designation, an idea that Friends of Cancer Research was instrumental in realizing, working with partners in advocacy, regulation, drug development, and bipartisan champions in Congress to advance this innovative concept, first as a scientific white paper and then through the congressional process to become federal law. Today, the program boasts more than 250 designations and over 100 approvals- and about half of the designations are for cancer treatments.   I am proud to have been a part of advancing this tool for patients and the FDA when I worked on the authorizing legislation during my tenure with the Senate Health, Education, Labor, and Pensions Committee.

Friends of Cancer Research was also actively engaged in developing parts of the 21st Century Cures Act, specifically intended to consider what more might be needed to help accelerate medical product development and bring new, safe and effective innovations and advances to patients who need them more efficiently. Of note, Cures authorized the FDA’s first inter-center institute that focuses on a specific disease rather than product type, the Oncology Center of Excellence. Breaking down institutional siloes in this way to leverage the combined skills of scientists and reviewers across the medical products centers has already yielded results for patients, as you will hear from Dr. Rick Pazdur later today.

Oncology leading the precision medicine revolution

This is truly an exciting time for cancer research as we see with so many discoveries being translated into important therapies.  Oncology is leading the precision medicine revolution as we move from a field based on tissue of origin towards one based on molecular aberrations such as ALK rearrangements, EGFR mutations and more recently microsatellite instability or mismatch repair deficiency, that is, a change that occurs in the DNA of certain cells in which the number of repeats of short, repeated sequences of DNA are different than the number of repeats that was in the DNA when it was inherited.

The many important cancer approvals last year and this year are ample testament to the high level of innovation we’re experiencing. In just a short period of time we’ve seen both the first and second gene therapy products for cancer, and the first tissue-agnostic cancer treatment for those tumors that have certain biomarkers irrespective of where in the body the tumor originates. And, so far this year, we’ve approved 12 novel oncology therapies, including the sixth immune checkpoint inhibitors targeting the PD-1 / PD-L1 pathway a blockade of anti-tumor immune responses that help the immune system recognize and attack cancer cells. If you drill down and look at the list of these approvals you see the agency’s regulatory efforts to be modern, flexible, and able to respond to changing needs and circumstances, while still fulfilling our public health mandate to ensure safe, effective and high-quality products for patients.

To harness these opportunities in science and technology, the FDA must create structures and processes that are able to keep pace with medical innovation.  And to keep pace requires that we build a dynamic regulatory environment across the continuum of medical product development from the premarket to the post-market phase. In today’s speech I’m going to discuss what the FDA is doing at different points along this continuum to advance new policies that will make medical product development more modern, more scientifically rigorous and more efficient.

Consider that tissue agnostic approval, which stemmed from the fact that tumors with a high microsatellite instability are more likely to respond to immune checkpoint inhibitors. Rather than requiring a separate development program for each disease site -- which may have taken many years and would likely never have happened at all for some of the rarer tumors -- we instead created a single therapeutic approach based on a solid scientific understanding of the underlying biology of microsatellite instability.

Or look at the ample use of novel endpoints in our recent approvals. Rather than overall survival, we accept progression-free survival, cytogenic response or pathologic complete response – and in one approval this year, we used metastasis-free survival for the first time as an endpoint. Now, given the seriousness of cancer, we’ve long accepted data from studies that don’t always conform to a randomized, controlled, double-blind clinical trial testing the product to placebo and an endpoint of overall survival, data which can take a decade or more to collect. So, it’s become commonplace for oncology studies to compare products to standard of care, to submit open label studies and to allow noninferiority comparisons. And this year we saw an approval based in part on data collected from patients who were enrolled in an expanded access program.

When your organization advanced the Breakthrough Therapy concept you quite rightly surmised that the FDA doesn’t simply review product submissions but can play an important role in helping to guide sponsors long before the submission itself.   As a result, companies with cutting-edge therapies which qualify for the breakthrough designation are now receiving much earlier interaction and advice from FDA staff.

But FDA can help enhance discovery and translation at even earlier stages of medical product development, as you can see with some of our recent work in oncology to reform the clinical trial process.

Setting the stage for modernizing clinical trials

The traditional drug development paradigm calls for three clinical trial phases - a small phase one tests safety and dosing, phase two tests short-term side effects and effectiveness over a range of doses and the large phase three assesses product efficacy and monitoring of adverse events. However, clinical trials are becoming more costly and complex to administer, which can make drug development more risky, uncertain and time consuming. Overly complex trials can also deter enrollment and delay completion.
Modern approaches to designing and conducting clinical trials can address some of these challenges. Today, the FDA is working across its medical product centers to facilitate innovative designs and patient-centered endpoints for drugs, biologics and medical devices. This includes the use of master clinical trial protocols, such as basket, umbrella and platform trials, which involve a common clinical trial infrastructure to study one or more interventions in multiple diseases or a single disease with multiple interventions, each targeting a biomarker-defined population or disease subtype.  For example, I-SPY 2 compares up to 12 experimental therapies in subgroups of patients with metastatic breast cancer with 10 distinct biomarker signatures. This hub and spoke design uses a common control, reducing the overall number of patients to be recruited and enrolled.

Seamless trials, used in oncology, are another novel approach. They compress the trial phases into one large, continuous trial. Since a lot of time and cost is spent between the starting and stopping of the traditional three phases, a seamless trial may be able to save time and reduce the number of patients needed for clinical development, thus reducing costs, while also enabling investigators to learn about a product’s efficacy and safety and help regulators and sponsors detect efficacy and safety signals earlier in the development process. Phase 1 trials that are based on an enrichment design – in other words, trials where the patients are selected for a treatment based on how their tumors express a specific biomarker – are associated with a significantly higher probability of demonstrating a clinical benefit than those that are not.

We know that FDA guidance can be very helpful, facilitating product development and providing the clarity that industry and researchers say they desire.  We recently issued for comment draft guidance on seamless trials and master protocols to expedite the development of cancer drugs. In addition, we issued a draft guidance on the use of placebos and blinding, which can pose ethical issues in cancer. FDA has generally advised that investigators use placebos only in selected circumstances. If possible, an active control is often preferred over placebo such as an open-label trial with physician’s choice of one of a few standard therapies or a design comparing investigational drug to placebo with each added to the standard of care. All of these draft guidance documents specifically address cancer drug development. In addition, we recently issued two other draft guidance documents on clinical trial modernization, including the use of adaptive designs, that addresses drug and biologic products more generally. Given the interest in novel complex innovative trial designs, including seamless trials, adaptive designs and biomarker enriched patient populations, we recently launched a pilot program that will give participating sponsors an opportunity to discuss these designs.

Broadening eligibility criteria for clinical trials

Traditional eligibility criteria for participation in a clinical trial sometimes excludes the patients most likely to be treated once the drug is on the market - the elderly, patients with poor performance status, organ dysfunction, brain metastasis, or other co- morbidities. The percentage of patients who can access investigational agents is necessarily limited as a result of these practices and enrollment accrual can be negatively impacted. This means investigators wind up chasing a small pool of potential patients, which can add to the cost and time of their clinical trials. FDA recognizes the problem and in a recent draft guidance addressed eligibility issues surrounding the inclusion of adolescents in adult oncology clinical trials. Some cancers in adolescents have similar histology and biologic behavior to those found in adults but because of their age, adolescents are generally not eligible for enrollment, which delays their access to potentially effective therapies. A new approach may help, and we welcome comment on this recent guidance document. I know that Friends of Cancer Research has an interest in eligibility criteria as well. Together with ASCO you recently recommended language for five guidance documents on ways to broaden eligibility criteria for cancer clinical trials regarding minimum age requirements for trial enrollment, HIV/AIDS status, brain metastases, organ dysfunction, and prior and concurrent malignancies. FDA is currently reviewing those recommendations.

Biomarkers

Endpoints are another important facet of trial design. As you all know, surrogate endpoints are an important tool that can sometimes be used instead of direct measure of clinical benefit to support accelerated approval or traditional approval. As I mentioned already, in cancer innovative endpoints such as progression free survival and pathologic complete response are putting treatments into the hands of high-risk patients, years before they would’ve been available using clinical endpoints, while still applying the FDA’s rigorous standards for safety and efficacy. FDA just published a list of surrogate endpoints which were the basis of approval or licensure of a drug or biologic product under accelerated or traditional approval. It provides useful information for drug developers on endpoints that may be considered.

Last month we issued a draft guidance on the use of minimal residual disease as a biomarker in clinical trials of drugs or biologics to treat specific blood cancers. Minimal residual disease is a general measure of tumor burden. As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of minimal residual disease data, the FDA identified a need to provide sponsors with guidance on the use of minimal residual disease as a biomarker in regulatory submissions.

FDA is also at work with Friends of Cancer Research and other partners on the development of a biomarker of tumor mutational burden to evaluate whether it may help predict the likelihood that a patient with cancer will benefit from immune-oncology therapies such as immune checkpoint inhibitors. Currently there is a lack of standardization for such calculation and reporting. Different tests may report different measurements and since there is currently no one way of calculating tumor mutational burden, it is difficult to use as a biomarker. To achieve consistency and accurate reporting across tests, I know Friends of Cancer Research believes, and FDA agrees, that it is imperative to create some sort of standardization to arrive at clinically-meaningful results, which will support informed decision-making for patients.
 

Patient reported outcomes

Cancer therapies are typically evaluated based on their ability to shrink a tumor or extend life. But cancer patients have other meaningful concerns as well, such as coping with disease symptoms and treatment-related side effects that can impact their ability to function or other aspects of their quality of life. FDA’s Oncology Center of Excellence has a Patient-Focused Drug Development Program that is investigating ways to standardize and improve our measurement of these patient experiences during both clinical trials and in real-world use following a drug’s approval. Such information can be used to better describe the risks and benefits of cancer therapies and inform oncology drug development. For example, the FDA used information gleaned from patient reported outcomes or PRO, as evidence to support regulatory risk-benefit decisions regarding ruxolitinib, after learning that there were important differences in pain, itching and night sweats in patients who took this drug to treat a rare disease of the bone marrow called myelofibrosis. FDA relied on another PRO measure to describe patient perception of the impact of crizotinib on certain visual side effects (e.g. floaters, shimmering lights, difficulty seeing at night), and FDA included this PRO information in the safety section of the FDA product label for this drug, which treats people with non-small cell lung cancer.
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Real-time review

Moving along the continuum of medical product development, let’s consider FDA’s advances at the early review stage. FDA is currently piloting what we call real-time oncology review.  Before the applicant formally submits the complete application, they submit the final version of the clinical protocol and analysis plan, key dataset packages, top-line safety and efficacy tables and figures and proposed labeling, giving FDA an early opportunity to address data quality and potential review issues. Along with real-time oncology review, we’re piloting a multidisciplinary review template we call the Assessment Aid, which focuses the FDA review document on critical thinking and consistency and decreases time spent on administrative tasks such as formatting. We’re currently testing these two approaches with supplements before potentially expanding it to novel drugs and biologics. A cancer drug was approved under these two pilots in July. By the time the applicant submitted the application, the agency’s review team had completed the analysis, and FDA was ready to approve it.

Gene therapy

Last year’s approval of the two CAR-T therapies for the treatment of advanced hematologic malignancies - initiated what many hope to be a steady wave of new gene therapy products, including many cancer treatments. Indeed, we currently count approximately 700 active investigational new drug applications for such products.

FDA responded in July to this fast-growing new field by issuing a suite of six draft scientific guidance documents that we believe, once finalized, will provide a modern, comprehensive, development framework for gene therapy.  In contrast to traditional drug review, some of the more challenging questions relate to product manufacturing and quality, or questions about the durability of response, which often can’t be fully answered in any reasonably sized pre-market trial, issues addressed in these documents. For some gene therapy products, we may need to accept some level of uncertainty around these questions at the time of approval with effective tools for reliable post-market follow-up. As we develop this evidence-based framework, we’re going to have to modernize how we approach certain aspects of these products in order to make sure our approach is tailored to the unique challenges and opportunities created by these innovations. Nevertheless, FDA will remain steadfastly committed to a regulatory path that maintains the agency’s gold standard for assuring safety and efficacy.

Diagnostics

In this age of precision cancer treatments, use of a specific test may help guide the use of a specific drug or biologic. FDA recently issued a draft guidance that outlines specific criteria under which sponsors may be able to include information about an investigational IVD in an investigational new drug application submission to either our Center for Drugs or Center for Biologics. Allowing this premarket information to be contained in a single application enables a more efficient review and further establishes the scientific relationship between the drug or biologic and the diagnostic used to select patients for treatment.

Next generation sequencing offers another powerful diagnostic tool for cancer. Tests we approved last year can scan for hundreds of tumor gene variants to help match patients with therapies or promising clinical trials. We want to encourage development of these important tests by enabling more efficient regulatory review. That’s why we’ve opted for a policy approach that can keep pace with these fast-moving technologies that give patients and clinicians confidence in their analytical and clinical validity, while still allowing these sequencing systems to be efficiently updated as new genes or gene variants or improved algorithms become known.

We issued final guidance in April that explains how test developers may rely on clinical evidence from FDA-recognized public databases to support clinical claims while providing assurance of the accurate clinical evaluation of the test results. A second guidance provided recommendations on the design, development and analytical validation of these tests. They are the latest examples of FDA’s efforts to create regulatory efficiencies in the development and review of NGS tests. In 2017, we authorized a third-party option for conducting reviews of NGS tumor profiling tests and outlined standardized benchmarks for carrier screening tests to allow for their marketing without prior agency review.

And important NGS products have already emerged – last year we approved tests that can scan for hundreds of tumor gene variants to help match patients with therapies or promising clinical trials. Earlier I mentioned a guidance on the use of minimal residual disease as a biomarker. Less than two months ago, we permitted the marketing of an NGS test for minimal residual disease in patients with acute lymphoblastic leukemia or multiple myeloma. It measures the amount of cancer cells remaining in a person’s bone marrow, either during or after treatment and is useful in evaluating whether patients may be at risk of disease recurrence.

Drug Labeling

I want to discuss one other aspect of our work across the continuum of medical product development – the FDA-approved product labeling, which provides essential information about the prescription drug. Friends of Cancer Research has developed proposals for the timely inclusion of new information on labels, particularly for generic drugs and older, off-patent product, based on a study which showed that most cancer drug labels are currently out of date.  We agree that updating labeling is important. The fiscal year 2019 budget gave FDA funding to update the labeling of generic drugs, and FDA plans to begin with cancer drugs. I’m sure Dr. Janet Woodcock will have more on that when she speaks to you later today.

Conclusion

Today I’ve taken you on a journey across the continuum of medical product development, discussing the many projects underway at FDA to build nothing less than a dynamic regulatory environment for those engaged in oncology research, development, and translation. Whether it is biomarker development or clinical trial modernization, all of our efforts are driven by the same motivating goal, making the development process more modern, more scientifically rigorous and more efficient so that more safe and effective therapies can be delivered to the hundreds of thousands of cancer patients who are anxiously awaiting them.

Thank you.