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Event Title
Remarks by FDA Commissioner Robert M. Califf to the 2022 NORD Breakthrough Summit
October 17, 2022

Speech by
Robert M. Califf, M.D., MACC

(Remarks as prepared for delivery)

Good morning.  It’s my great pleasure to be with you today.  The last time I had the opportunity to speak with this group was in 2016, during my first stint as Commissioner. I’m happy to say that a lot of progress has been made since then, but I also want to acknowledge that we have a long way to go.

Indeed, the work of this organization has only grown more significant in those six years, as both the challenges and the opportunities in the world of bioscience and therapeutics affecting rare diseases have grown. Your efforts to build collaborations and represent and support the interests and needs of patients in finding new opportunities, treatments, and cures are even more critical today.  

I want to acknowledge the work of everyone here who is so committed to these goals – patient and health organizations, clinicians and researchers, drug and product developers, and scientists, regulators, and others across government.  But I especially want to thank the patients and their families who devote such a significant part of your lives to the search for new treatments and cures and to the implementation of proven treatments in clinical care.   

I was impressed to see the conference kick off with the patient/caregiver opening address. This speech and its placement exemplify and underscore the critical role played by patients in this work.  Patient involvement and engagement is a critical component of our efforts at the FDA and across the entire public health continuum, including our rare disease activities. 
By listening to patient voices and by incorporating and learning from that engagement and guidance, we gain a better understanding of diseases and their treatments. The experience and input of patients can play a key role in scientific discovery, clinical evaluation of interventions, and other aspects of medicine and science, from disease diagnosis to product development to the review and decisions about approval of safe and effective treatments.  It can support and strengthen the empirical evidence that plays such an essential role in our regulatory decision-making.  And it can help spur the development of medical products and treatments and even change and strengthen the systems we use to accomplish this.  A common understanding of how to develop a facilitating ecosystem would create a rising tide that would raise all boats in the pursuit of effective treatment and cures for rare diseases.
I don’t need to tell this group that the role and impact of patients in the rare disease can be especially significant because of the unique challenges associated with the relatively small populations affected by these diseases. You know the numbers all too well.  Over 7,000 rare diseases affecting more than 30 million people in the United States, with approximately half affecting children.  Perhaps most troubling is that the vast majority of rare diseases do not yet have approved treatments. 
That’s not to say that we’ve haven’t come a great distance in some areas.  Since passage of the Orphan Drug Act in 1983, we’ve seen over 1,000 orphan products approvals.  In 2021, CDER approved 50 novel drugs, either as new molecular entities under New Drug Applications, or as new biological products under Biologics License Applications, 52% of which were approved to treat rare or “orphan” diseases. And the Center for Biologics Evaluation and Research approved 10 novel biologics, five of which were approved to treat orphan diseases.  And we’ve continued to see important progress in rare disease product development this year. 

And yet, against this backdrop of success -- due in large part to your extraordinary work and commitment -- much more needs to be done.  We still face enormous scientific challenges in the development of treatments for rare diseases, which come with significant costs.  The nature of rare diseases itself, along with the small patient populations, means there are a limited number of people available to participate clinical trials.  The challenges of endpoint selection in a clinical trial, especially when there is a limited understanding of a disease’s underlying biology and natural history present additional hurdles.  
While we will continue to see important and often remarkable progress, we also need to acknowledge these continuing challenges, including the fact that the vast majority of drugs evaluated in early phase human testing will probably not make it to market because of unexpected toxicity or failure to have the expected beneficial effect on clinical outcome. 

As we work to develop new approaches and responses to these tough medical and scientific challenges, it is imperative that we continue to build an effective ecosystem that is centered on patients, but also involves collaboration among patients and their advocates, representatives of industry, government, researchers, academia, and many other stakeholders.  Only through these collaborations can we develop efficient and respectful approaches to the necessary clinical trials to sort through treatments and quickly identify those that turn out to be effective while getting rid of ineffective or dangerous treatments.  NORD has played an essential role in building this kind of ecosystem, and we need to continue to strengthen and expand it.  
A key piece of this system involves something that has been of particular importance to me throughout my professional life -- the need to strengthen the systems we use to generate and gather new and better data and ensure that we have the most reliable evidence to inform and improve the decisions we make.   
As I am fond of saying, “In God we trust, all others must bring high quality evidence.” The more complex the medical challenges, the more important it is that we expand the sources, quality, and types of data we use to analyze and overcome them.  Nowhere is that challenge clearer than in the rare disease area, and it underscores one of the essential aspects of the meaning of good data.  For our purposes, the data has to be applicable and relevant to the population being studied, and this population should be representative of the population intended to get the intervention or included in a manner that allows confidence about extrapolation to the population intended to receive the intervention.   
That’s why the role and impact of Real World Data (or RWD) is so important.  As most of you know, RWD are data relating to patient health status and/or the delivery of health care that is routinely collected from a variety of sources, including information obtained at the point of care.  It’s basically all data not collected in a specialized research environment.  The collection and analysis of RWD, using an appropriate study design, in turn help generate real-world evidence (or RWE), which is the clinical evidence relating to a medical product’s use. 

Together, RWE and RWD can provide mechanisms to accelerate the development of therapies that improve the lives of patients with rare diseases.  For example, real world data could be used to expedite the identification and enrollment of patients into clinical studies.  And it can inform the design of traditional clinical trials, such as the selection of endpoints and trial duration.  

A further important benefit of the use of RWD and RWE is the potential it offers to reveal previously unknown interactions of drugs to patients, which can both improve patient care and help make clinical trials more efficient and productive.  It’s important to note, however, that there are important considerations, such as whether real world data are fit for a particular use. 
Later in this meeting you’ll have the opportunity to hear from FDA staff during an FDA plenary panel discussion entitled “Real World Data/Real World Results” on the many ways we are working to access and apply these types of data.   
But now I want to spend a few minutes focusing on one important area that advances rare disease drug development -- when we get it right – biomarker development.   
As many of you know, biomarkers are powerful tools in our armamentarium for facilitating the discovery and development of new cures, and real world data may help us connect biomarkers to clinical outcomes that matter to patients.  A biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions. Biomarkers may include molecular, histologic, radiographic, or physiologic characteristics. A biomarker is not a measure of how an individual feels, functions, or survives. Good biomarkers can help us tell more quickly whether or not a drug is engaging the right target, and what the best dose might be. The best biomarkers are backed by solid translational science programs in development and are reasonably likely to predict clinical outcomes.   Developing useful biomarkers is hard work and it takes extensive collaboration and attention to detail to get it right.

Biomarkers are not the only endpoints in rare diseases, of course.  Another type of endpoint is a clinical outcome assessment, which measures how an individual feels, functions or survives. One way the FDA is working to advance this approach is through CDER’s Standard Core Clinical Outcome and Related Endpoints Grant Program, which currently has funded the development of five core sets of clinical outcome assessments. Three of these grants are related to rare diseases. In addition, a new combined CDER/CBER commitment funded through the Prescription Drug User Fee Act (PDUFA VII), the Rare Disease Endpoint Advancement (RDEA) Pilot Program will support novel efficacy endpoint development for drugs that treat rare diseases. 

The FDA also collaborates with the Critical Path Institute (or C-Path), through initiatives like the Rare Disease Cures Accelerator Data and Analytics Platform, which provides a centralized and standardized infrastructure to support and accelerate rare disease characterization, with the goal of accelerating therapy development across rare diseases. I’m pleased to note that NORD is also a partner in this project.  

What all of these efforts underscore is that all data generated from patients with rare diseases are critically important. That’s why all stakeholders are strongly encouraged to collaborate and share data with trusted partners. 
I just mentioned the grants FDA awards related to clinical outcome assessments.  But those are just a few of the many grants that the FDA provides to support a variety of rare disease research. The FDA’s Orphan Products Grants Program provides important funding to support rare disease research – more than $480 million for more than 780 rare disease studies since it began in 1983, funding trials that have facilitated the approval of more than 80 rare disease products.  

Today, I’m pleased to announce the award of 19 new grants (11 clinical trials and 8 natural history studies) that focus on unmet needs of rare diseases.  Seven of the awards fund studies of rare cancers.  The natural history study grants support innovative research to inform medical product development by better understanding how specific rare diseases progress over time, including related to rare neurodegenerative diseases. And several studies seek to characterize certain subgroups within a disease and identify novel clinical outcome measures and biomarkers, which have the potential to improve the current standard of care and inform future drug development, including gene therapies. 

We’re also announcing today the FDA Rare Neurodegenerative Disease Grant Program awards, which provides grants and contracts to public and private entities to cover costs of research on, and development of, interventions intended to prevent, diagnose, mitigate, treat, or cure ALS and other rare neurodegenerative diseases.  This program is based in part on the Accelerating Access to Critical Therapies for ALS law signed into law by President Biden last December.  
I urge you to take a closer look at these grants and contracts.  It's important that we hear from stakeholders in this field, which is why we’ve opened a call for comments on current funding needs in the rare neurodegenerative disease space that could be supported by grants from the Office of Orphan Products Development. 

As I said at the outset of my remarks, rare diseases activities benefit greatly from collaboration and the sharing of data and other information.  There are a number of new collaborative efforts that we’ve recently unveiled that strengthen these collaborations. 
Last October, for example, CBER, and NIH launched The Bespoke Gene Therapy Consortium. This effort brings together 27 partners that includes multiple NIH Institutes, industry organizations, academic investigators, and a number of patient advocacy groups to help ease the roadblocks to gene therapy development for ultra-rare diseases.  The word bespoke is intriguing—its common meaning is “made for a particular customer or user.”  When we tailor a gene therapy for an individual there is the possibility of a unique cure, but the methods of predicting success will require deep creativity and collaboration.

As you know, the promise of gene therapy technologies is enormous, putting transformative treatments for many rare diseases within reach. But as with many rare diseases, the costs and other challenges are enormous.  The objective of this consortium is to use a common set of procedures in a pre-competitive environment to drive innovation and promote access to individualized gene therapies.  This effort could bring a radical change to the bespoke therapy model and provide enormous benefits to patients and families looking for solutions in the ultra-rare gene therapy space.  

I should point out that while the BGTC initiative is focused on ultra-rare diseases, we anticipate that the technologies, paradigms, and information gained from the program can be applied more broadly to rare and even common disorders.  What we learn will have a much broader impact on the overall gene therapy field. 

I want to briefly mention our international collaboration in the area of rare diseases.  In 2016 we formed the International Rare Disease Cluster, with members including the FDA, the European Medicines Agency, and Health Canada.  Collaboration among international regulators is important to support rare disease product development.
This is something our Oncology Center of Excellence (OCE) has focused on with Project Orbis, initiated in 2019 to provide a framework for concurrent submission and review of oncology products among international partners.  Pivotal clinical trials in oncology are commonly conducted internationally and future drug development may benefit by establishing a greater uniformity of new global standards of treatment, leading to the optimal design of these important trials. Since its inception, Project Orbis has received many oncology marketing applications and led to the approval of numerous oncology drugs for patients across the world.  

In short, a lot of good things are happening in this area. There is enormous potential.  There is enormous energy and commitment from this community.  And there are increasing opportunities for powerful collaboration that we must build on.   
Collaboration is already a fundamental concept in the FDA’s work.  Every day, our scientists, public health experts, and regulators work across government, and with patients and patient advocacy groups to find new ways to speed the development of treatments for individual diseases. And the goal is to share this across the rare disease ecosystem.  
Our staff brings skills and knowledge to the table that can facilitate development of effective interventions while also regulating them—a difficult, but essential balancing act.  For example, awareness and understanding of the success and failure of all products in development enables FDA to guide programs without revealing confidential trade secret information.  By providing greater regulatory clarity we can help identify the best and most efficient pathways, prevent waste or duplicative efforts, ensure speedy development of the best and most effective products and, very importantly—prevent enrollment of patients into clinical studies that could cause harm based on knowledge of previous failures.  By building partnerships with other stakeholders we can fulfill the promise of science and generate actionable solutions for the development of new treatments.  
In addition to providing greater regulatory clarity, we are also working in the rare disease space to embrace greater regulatory flexibility to help meet unmet medical needs.  As you know all too well, rare diseases require a unique balance between regulatory flexibility and the scientific evidence necessary to ensure that a product is safe and effective.  

We recognize that many people with serious diseases and few or no approved therapies are willing to accept a higher degree of uncertainty on the path to develop treatments.  It is a calculation that involves closely looking at and balancing scientific integrity, unmet needs, and risk.  Moreover, it is a calibration that can change based on the indication and the drug under study.  
There are a number of regulatory flexibilities the FDA can apply in the rare disease context, for example accepting clinical trials that have lower sample sizes. FDA recognizes that certain aspects of drug development that are feasible for common diseases may not be feasible for rare diseases and that development challenges are often greater with increasing rarity of the disease. FDA will continue to apply flexibility in these situations to address particular challenges posed by each disease
It’s important to underscore that none of these approaches mean the integrity of the results is compromised; indeed, these approaches are designed and intended to help generate more high quality evidence that could support a drug approval.  As with all of our decisions, they will be based on the best available science.  

I want to call your attention to an issue that we need to address as soon as possible – accelerated approvals. While the process is intended to ensure the integrity of the data and analyses, the fact is that accelerated approvals based on biomarkers leave more uncertainty about the true risk and benefit.  And regardless, many of these interventions will be approved based on a limited time frame of a clinical trial.  And yet, the potential effects, both benefits and risks, will be manifested over a lifetime.   Through the same type of collaboration that will lead to discovery and introduction of new treatments, we need a system of evidence generation that provides the confirmation of benefits and risks over years.
As I hope my remarks today have made clear, we’ve seen great success in finding treatments for rare diseases and we have enormous potential for future developments.  But to fulfill this potential requires not just action by drug developers, the FDA, or the patient community, but will necessitate engagement and collaboration across the entire spectrum of those involved in this work.  
These opportunities are especially promising and important in rare diseases precisely because the challenges involved with the development of new treatments is so high. Working together we can ensure that our efforts are coordinated, not diluted, thereby maximizing our strength, capabilities, and potential.   
Thank you again for your commitment to this work.  I look forward to our continued collaboration in the generation of essential evidence and the creation of holistic ecosystem that supports success. 

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