- Speech by
Deputy Commissioner for Policy, Legislation, and International Affairs - Food and Drug Administration ( March 2019 - January 2021 )
Remarks by Anna Abram
Deputy Commissioner for Policy, Legislation, and International Affairs
16th Annual Accelerating Anticancer Agent Development and Validation Workshop
Keynote Address: FDA Policy Impacting the Development and Availability of Cancer Drugs and Diagnostics
May 9, 2019
(Remarks as prepared for delivery)
Thank you. It’s a pleasure to be here to talk about what FDA is doing regarding the development and availability of cancer drugs and diagnostics and to acknowledge the important work that all of you do.
This is the 16th year for this workshop, which provides access to FDA reviewers and staff from all disciplines to promote interaction and enhanced learning.
When AAADV first met in 2003, there were only a handful of FDA-approved targeted drug therapies available, including two blockbuster immunotherapies and the first therapeutic monoclonal antibodies to treat lymphoma and breast cancer. In that same year, scientists announced they had successfully mapped the 3 billion DNA letters in the human genome, which paved the way for research to identify the genetic defects that fuel many cancers and for new ways of screening for and treating the disease.
Much has happened in oncology development since then. Advances in biology and immunology have continued to refine our understanding of cancer.
In the last two years alone, FDA approved new molecular entities to treat a host of cancers including new therapies for leukemia, lymphoma, ovarian, liver, breast, colorectal and prostate cancer, the first cancer treatments based on a genetic feature of a cancer rather than the location of the body where the tumor originated, and the first one-time gene therapy treatments that use a patient’s own genetically engineered T-cells to recognize and destroy cancer cells.
In all, FDA approved a total of 35 new molecular entities for oncology indications during that two-year period – a remarkable number when you consider that oncologists had only about three dozen drugs available to treat cancer in all of its many manifestations in the early 1980s.
With so many more treatment options available, the outlook for many patients with cancer is much brighter than it was decades ago. From 1990 through 2014, the overall cancer death rate in the U.S. fell by 25 percent. In 2014, the number of people living beyond a cancer diagnosis reached 14.5 million and by 2024, that number is expected to climb to approximately 19 million.
Death rates for the four most commonly diagnosed cancers in the United States—breast, colorectal, lung, and prostate cancer—have been on the decline for more than a decade.
And yet, despite all the encouraging results, death rates from other forms of cancer, most notably brain, liver and uterine cancer have actually been increasing in recent years. We’ve seen great progress for patients with cancer when diagnosed and treated at an early stage, and over the past few years have approved an unprecedented number of treatments for patients with cancer that has spread to distant sites. But unfortunately, most metastatic solid tumors remain incurable. And translating advances in biology and immunology into effective cancer treatments remains difficult. Thus, there’s still much more to be done to combat this deadly disease.
FDA’s role in oncology product development
The development of lifesaving products for patients depends on the success of moving an idea from “bench to bedside” in a process that includes preclinical testing, meaningful clinical trials, robust data analyses, and appropriate regulatory mechanisms that balance patient’s needs with product effectiveness and safety.
Today, I’m going to talk about what FDA is doing to advance oncology drug development, everything from the way we’re organized to the steps we’re taking to modernize clinical trials and encourage greater patient participation in clinical trials. Indeed, over the past few days, I hope you have come to appreciate that FDA plays a pivotal role at many steps along the life-cycle of oncology products.
For example, during the development phase, we provide early consultation and clear written guidance on a range of topics which are released in draft form first to obtain public input. In 2018 alone, FDA issued 11 oncology specific guidances that, taken together, reflect FDA’s flexible and sensible approach to drug development.
In addition, drugs that address an unmet medical need in the treatment of a serious or life-threatening condition may qualify for one or more of FDA’s expedited development and review programs. These include: Fast-track designation, where applicants may meet frequently with the review team prior to filing an investigational new drug application as well as for end of phase 1 and end of phase 2 meetings to discuss study design and other issues;
Breakthrough therapy designation – essentially an all-hands-on-deck approach – that offers intense advice and consultation to sponsors; Accelerated approval based on a surrogate endpoint; and Priority review, which is a shorter review timetable.
One of the challenges we face as regulators is keeping up with rapidly changing science and technology. We work hard to keep up, adapting our practices and policies, if need be, as science and medicine evolve to fit our changing understanding of cancer and how to treat it. Consider the steps we have taken in the wake of recent approvals of CAR-T therapies for the treatment of advanced hematologic malignancies. Regulatory certainty is important in product development. FDA knows from experience that emerging technologies benefit from regulatory clarity and that these recent approvals were likely to touch off what we expect will be a steady wave of new gene therapy products, including many cancer treatments.
That’s why we issued a suite of six scientific draft guidance documents in July of last year that we believe, once finalized, will provide a modern and comprehensive development framework for gene therapy. For gene therapy, some of the more challenging questions relate to product manufacturing and quality, and questions about the durability of response. This means there will be some level of uncertainty around such questions at the time of approval with effective tools for reliable post-market follow-up, while still maintaining our gold standard for assuring safety and efficacy, issues we addressed in these guidances.
FDA’s Oncology Center of Excellence, authorized under the 21st Century Cures Act, has been pivotal in helping to streamline FDA’s approach to novel cancer development and product review. In my opinion, OCE serves as an important catalyst when it comes to our oncology work. OCE leverages the combined skills of the agency’s regulatory scientists and reviewers with expertise in drugs, biologics and devices to support an integrated approach to various cancer issues and has over 20 clinicians and scientists who are assigned to maintain a high level of expertise and engagement in multiple disease and research disciplines.
OCE has programs in precision oncology, immuno-oncology, cell and gene therapy and pediatric oncology. It also sponsors dozens of scientific workshops every year and promotes research in regulatory science. Moreover, all of the oncology product submissions seeking expedited development and review are coordinated through the Center.
To further efficiently review, OCE is piloting a new review program called Real-Time Oncology Review – allowing FDA to access key data prior to the official submission of the application. 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. This allows the review team to begin their review earlier and communicate with the sponsor prior to the application’s actual submission.
OCE successfully piloted this approach in the expanded approval of a monoclonal antibody to treat patients with newly diagnosed peripheral T-cell lymphoma. As a result, FDA was able to approve the indication within 2 weeks of the completed application’s submission.
Clinical trial modernization
We know it can take about 9.5 years or so to develop a cytotoxic agent and about 5.5 years for a targeted therapy. FDA has been looking at ways it can help to further compress this development cycle.
The traditional drug development paradigm involves three clinical trial phases – a small phase one trial, which tests safety and dosing; phase two trials, which test short-term side effects and activity over a range of doses; and large phase three trials that assesses whether the product’s benefits outweigh its risks. However, clinical trials can be costly and challenging to administer, which can make drug development risky, uncertain and time consuming and can also deter enrollment and delay completion.
FDA has been working to modernize the design and conduct of clinical trials that can address some of these challenges. This includes the use of master 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. One well known master protocol is I-SPY 2, which compares up to 12 experimental therapies in subgroups of patients with early high-risk breast cancer with 10 distinct biomarker signatures. This hub and spoke design uses a common control, decreasing the number of patients needed for enrollment and reducing time in selecting treatments for further testing in phase 3 trials, while providing statistical rigor in formulating decisions to screen treatments.
Another way we’re working to modernize the way clinical trials are conducted is through expansion cohort trials that compress the traditional three phases of trials into one continuous trial. Such study designs employ multiple, concurrently accruing patient cohorts with individual cohorts assessing different aspects of a drug’s safety pharmacokinetics and anti-tumor activity. We issued a guidance document in August of last year on the use of expansion cohorts in first-in-human clinical trials. A lot of the time and cost of clinical development is spent waiting in between the start and end of the phases of trials. Expansion cohort trials can help bring efficiency to drug development, potentially reducing development costs and time.
Most recently we’ve provided guidance on the use of enrichment strategies that can be helpful in identifying groups of patients based on clinical laboratory tests, genomics or proteomics, who may benefit the most from a targeted cancer therapy. Enrichment can make it easier to detect a drug’s effect in a biomarker selected population for example those with Her2Neu positive breast cancer than it would be in a larger population that hasn’t been prespecified, allowing for a shorter and smaller drug trial.
Given the seriousness of cancer, FDA has long accepted data from studies that don’t always conform to a randomized, controlled, double-blind clinical trial testing the product to placebo, which we generally advise only in selected circumstances. Instead, we now generally see oncology studies to compare products to standard of care, to submit open label studies and to allow noninferiority comparisons. For example, in 2018, we approved a drug based in part on data collected from patients enrolled in an expanded access program.
Just as studies in cancer don’t conform to a randomized controlled double-blind clinical trial, they also don’t necessarily conform to the use of clinical endpoints such as overall survival. Thus, we have accepted progression-free survival, cytogenic response, pathologic complete response and more recently metastasis-free survival as a measure of clinical benefit to support accelerated approval or traditional approval. This allows us to put treatments into the hands of patients, years before they would have been available using clinical benefit endpoints such as overall survival, while still applying the FDA’s rigorous standards for safety and efficacy.
Last year we 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. The list provides useful information for drug developers on endpoints that may be considered. We also issued revised guidance that outlines our thinking on oncology endpoints based on the specific context of use, as well as the advantages and disadvantages of these endpoints in clinical development programs. And in March, we issued draft guidance on an endpoint known as minimal residual disease, a general measure of tumor burden in development programs for drugs or biologics to treat specific blood cancers.
There’s also been considerable interest in biomarkers that might inform the development of drugs that treat biomarker directed tissue agnostic indications, in the wake of two recent approvals of treatments based on a genetic feature of a cancer rather than the location of the body where the tumor originated. Last week, we further advanced these discussions by jointly sponsoring a workshop on the topic.
It’s important for the clinical community to know about the quality of the evidence supporting a drug approval and the extent to which any uncertainty still exists about the product’s safety and effectiveness. FDA grants accelerated approval based on an effect on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict clinical benefit, with the requirement that the sponsor conduct a post-market trial to confirm the results. We recently issued final guidance to help ensure that a product’s labeling provides actionable and complete information about the clinical evidence supporting approval and clearly states that post-market commitments may have to be met for an indication to remain approved. We also provided labeling recommendations for the circumstances when a drug or indication approved under accelerated approval may be withdrawn because it fails to demonstrate clinical benefit in post-market, confirmatory trials.
Patient participation in clinical trials
One of the challenges of drug development is finding enough patients to participate in a pivotal clinical trial. It’s been estimated that no more than about 5 percent of all adult cancer patients are enrolled in cancer clinical trials even though 70% of Americans say they are at least inclined or even very willing to participate in a trial. Traditional eligibility criteria sometimes exclude those patients who are most likely to be treated once the drug is on the market. The percentage of patients who can access investigators 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.
In March, FDA issued four draft guidances on ways to broaden eligibility criteria for patients with HIV, Hepatitis B Virus or Hepatitis C Virus, for patients with organ dysfunction or prior or concurrent malignancies, for patients with brain metastases, and for the inclusion of pediatric patients. The four draft guidances were developed with the input from the American Society of Clinical Oncology and Friends of Cancer Research.
Also, in March, we issued final guidance on the inclusion of adolescent patients in adult oncology trials. Adolescent patients, because of their age, have historically not been eligible for enrollment in adult oncology studies even though their histology and biologic behavior is similar to those found in adults. Also, the initial pediatric trials for many drugs are conducted often years after the drug is approved in adults. Revamping inclusion criteria is one way to help address this problem.
FDA is also aware that in many cases more than half of the cancer patients enrolled in pivotal clinical trials are located in other countries. FDA supports the use of foreign data; however, having such studies in countries with regulatory systems that may differ from ours requires FDA outreach and monitoring. The Office of Global Policy and Strategy, which is part of my office, the Office of Policy, Legislation, and International Affairs, plays a pivotal role in this effort.
While our new guidances on eligibility criteria may well increase the percentage of patients who participate in pivotal clinical trials, we recognize there are also various structural, clinical, socioeconomic, demographic and attitudinal barriers to participation that lower the participation rates of some patient populations and we have taken some steps to encourage greater clinical trial diversity. Our Drug Trial Snapshots, posted for each new molecular entity we approve, breaks down the percentage of subgroups who were enrolled in the drug’s pivotal clinical trial. Our hope is that such transparency will encourage sponsors to seek greater diversity when they enroll patients.
Patient-focused drug development
Certainly, one of the changes that we’ve seen since the first AAADV workshops is the evolving role of cancer patients in drug development. 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 quality of life. As a result, it is crucial to have a systematic approach for product development and evaluation to help ensure that patients’ experiences, perspectives, needs, and priorities are captured and meaningfully incorporated.
FDA’s Oncology Center of Excellence has a Patient-Focused Drug Development Program which fosters collaboration between FDA Centers and external stakeholders involved in patient outcomes research in cancer populations. Through this program, we have been specifically targeting a core set of outcomes that include disease symptoms, symptomatic adverse events and physical function. This data is being used as part of the benefit-risk assessment in new drug applications and in a small percentage of cases has been included in FDA product labels.
Since 2010, eight labels for cancer indications have incorporated patient reported outcomes or patient reported outcome results. Before that, only 2 labels for cancer indications did so. Consider two examples of patient reported outcome data in drug labels reviewed just in the last five years. A formulation of a drug that can be administered subcutaneously included data on what route of drug administration patients preferred, and two drugs treating a form of metastatic non-small cell lung cancer included data from patients reporting whether or not they had experienced shortness of breath.
Today, it’s the rare cancer trial that doesn’t include patient reported outcome data to inform both regulatory and payer decision making, and we expect to see even greater use of patient reported outcome data going forward. The FDA’s Oncology Center of Excellence has created several patient reported outcome review resources and has hired a social scientist with expertise in patient reported outcome tool development and data analysis. FDA is also actively engaged in efforts to advance the measurement, analysis, and communication of patient reported outcome data.
On July 12 of this year, we will be hosting our 4th public workshop on patient reported outcomes in cancer trials to further this work.
Finally, I’d like to conclude by highlighting two patient-focused projects piloted by OCE: Project Renewal, and Project Facilitate.
The aim of Project Renewal is to update the often-outdated product labeling that currently exists for off-patent, typically generic, oncology products, which rarely reflect new insights on pharmacology, toxicology, safety drug interactions, observational data and clinical trials, information that could reduce potential risk to patients and may even support new indications.
Under Project Renewal, a contractor’s scientific experts will review certain of these long-standing, typically off-patent oncology products that have accumulated substantial safety and efficacy evidence and will recommend revisions to their labels that FDA can review, including updates related to safety, dose and administration, and additional indications in common use. If certain indications are no longer relevant to current oncology practice, the reviewers may recommend that they be removed. Following the expert review, FDA will work with sponsors to update the labeling for the studied products.
FDA hopes this process will add value to the labeling update process, encourage the oncology community to familiarize themselves with the product label and create educational opportunities for early career researchers. Our long-term intent is to establish a repeatable process for making updates so that we can ultimately create living product labels.
FDA’s other initiative, Project Facilitate, is a pilot program aimed at helping patients with cancer obtain easier access to unapproved oncology products through our existing expanded access program. Under Project Facilitate, we are proposing to establish a call center that would funnel telephone calls from providers to a single call center where regulatory project managers will help walk them through the single-patient IND request form and guide them through the process to request a single-patient IND for an investigational oncology product for their patients.
Under Project Facilitate, officials staffing the call center will provide the doctor with someone to contact at the drug company and a listing of institutional review boards (IRBs) that review single-patient INDs, will stay in contact with the doctor throughout that process and, once those hurdles are cleared, will help the doctor fill out the necessary form –Form 3926, which FDA recently simplified. As most of you know, FDA approves more than 99% of the single-patient IND requests and does so in less than 24 hours, but we don’t have complete information on manufacturers that agree to supply their product under a single-patient IND and if they don’t, why they refuse to do so. We hope to collect some of this important information under Project Facilitate.
For those who are interested in this pilot program, we’ll be holding a public workshop on the topic on May 16 at our White Oak campus.
There is much reason for optimism about the future of oncology product development. Today, oncologists enjoy a broader range of products to treat cancer including multiple cytotoxic drugs, targeted drug therapies, and immunotherapies. And there are many products in the pipeline with 1,500 clinical trials in immune-oncology alone.
As I’ve mentioned today, FDA is committed to encouraging oncology product development in many ways along the product lifecycle. We’ve proposed guidance on how to modernize clinical trials, and how to better measure patient outcomes. We’re looking at ways to collect data through simple pragmatic trials that rely on real world evidence, to improve clinical trial participation and to better convey information to patients and clinicians. Moreover, as a science-based agency, we have mechanisms in place to make sure FDA stays current with changing science and medicine. It’s all part of what we’re doing to be ready for the many advances in cancer biology and therapeutics to come.
Thank you for your work on behalf of cancer patients across our country.