FDA Commissioner Dr. Robert Califf delivered the following keynote address today at NORD’s 2016 Rare Diseases and Orphan Products Breakthrough Summit. The Summit was attended by 600 people from all areas of rare diseases. NORD, the leading independent nonprofit dedicated to helping people with rare diseases, hosts the 2-day event each year to bring all stakeholders together and identify new areas for collaboration and progress.
This speech is provided on the NORD website with permission from FDA.
Speech by Robert M. Califf, M.D.
Commissioner of Food and Drugs
2016 National Organization for Rare Disorders (NORD) Summit
October 17, 2016
“Critical Lessons about Rare Disease Drug Development”
Thank you Peter [Saltonstall] for that kind introduction, and for your leadership of this great organization.
NORD does a remarkable job marshaling the strengths of the rare disease community, effectively representing the needs and interests of patients, and advancing the goal of finding new opportunities, treatments, and cures.
As I look out across this committed and engaged audience, it reinforces my understanding of how important strong and effective collaborations are to create success in the world of bioscience and therapeutics, especially where relatively small populations are affected.
This organization brings together so many different experts in rare disease from across the spectrum. This meeting includes scientific and medical researchers, representatives from both small and large companies, investors and potential investors, healthcare organizations, and government officials including FDA and NIH staff. And, most importantly, it involves patients and caregivers, who live with these diseases every day. They provide the most valuable resource for finding answers to how best to fight these diseases.
The Strength and Success of the Rare Disease Community
All of you collectively make up the rare disease community. Through my career, both at FDA, and in my work in practice as a clinician, teacher and researcher, I’ve seen how this community has demonstrated the power of patient advocacy. Patients and families have created an extraordinary and disciplined movement to get information and seek answers, to stimulate research and develop treatments … always focused on the concrete goal of improving the health of people with rare diseases so that they and their loved ones can experience a better life.
To take just one example, consider the Orphan Drug Act, which has made such a difference to so many by spurring the development of new treatments. If not for this community, this law would not even exist.
So I commend you for your strength, your collaboration, and your successes.
Now I’m sure it can sometimes seem difficult to chart those successes in the face of continuing struggles and the complexity of the problems you come up against. There are many failures, despite the well-intentioned efforts of countless numbers of bright and dedicated people.
But there has indeed been important progress – important not just to individual families, but also to the future of the development of underlying answers to the treatment and cure of rare diseases.
One clear conclusion that can be drawn from this success directly correlates to your leadership in this area. And that is that we are in the midst of extraordinary intellectual ferment in this area, resulting in scientific innovation and product and technology development.
Now that we are entering an era of remarkable progress, we want to keep the support at the highest level possible.
For more than 30 years — three decades — FDA has actively helped to translate research and development into new safe and effective medical products for rare diseases through its Orphan Products Clinical Trials Grants Program. This program has provided more than $370 million to fund over 590 new clinical studies and supported the marketing approval of more than 55 products. In fact, in 2015 alone, five of the studies funded by this program supported product approvals, including treatments for neuroblastoma, lymphangioleiomyomatosis, hypoparathyroidism, and hypophosphatasia.
I’m pleased to announce that additional FDA funding is on its way through 21 new grants to support clinical trials for rare disease product development. These new grants, totalling more than $23 million over four years, are going to principal investigators from academia and industry for research that spans domestic and international clinical sites.
And FDA support doesn’t end there. This year, FDA launched a new Orphan Products Natural History Grant Program to complement the important work that NORD and others are doing to promote the development of natural histories which provide more detailed information on how diseases develop and progress over time. We plan to directly fund targeted studies that characterize the natural history of specific rare diseases, identify genotypic and phenotypic subpopulations, and develop or validate clinical outcome measures, biomarkers, and companion diagnostics.
Developing robust natural history data continuously, before, during and after drug development, helps provide essential information to design the best approaches to development of effective treatment and deploy those treatments in practice. Charting the natural course of disease over time – how the disease manifests itself, what we should measure in terms of improvement or deterioration, what is the right endpoint, and the right population to target—provides the fundamental basis for understanding the goals of drug and device development and for determining which treatments are effective. This natural history knowledge is essential information that critically informs drug development from the outset.
I want to especially acknowledge two people whose work at the Federal level will be critical to the success of your efforts. They are both amazingly bright and intelligent individuals who seem to have unbounded energy to work with you and other constituents in the ecosystem – researchers, industry and federal agencies – to make progress across the boundaries of science.
Dr. Gayatri Rao is the Director of the Office of Orphan Products Development at FDA. She is a great advocate for your community and a committed leader at FDA with whom I’ve had the pleasure of working with for a year and a half now.
Dr. Petra Kaufman at NIH heads up both the Clinical and Translational Sciences program and the Office of Rare Diseases Research there. Petra is an energetic and visionary leader with a strong base as a neurologist caring for patients with rare diseases.
There is much to be gained by effective interaction between FDA and NIH, and these are two people who know how to lead and collaborate
In addition, Congress and the FDA have worked together with advocacy groups and the clinical community to develop a series of incentives and expedited pathways for promising therapies for diseases without meaningful effective therapies and with dire prognoses.
Congress, through the authority of the FDA, provides a number of incentives to promote the development of drugs and biologics for rare diseases, including tax credits for clinical trial costs, waiver of marketing application fees, and seven years of exclusivity, through the orphan drug designation program.
And these incentives are making a difference and stimulating development. The number of designations for orphan drugs continues to grow at an extraordinary rate. In 2014, we saw a 30 percent increase over the prior year’s record number of designations. That record in turn was broken the very next year when we received close to 470 requests. And this record pace has continued this year.
Lessons for Future Progress
All of this leads to the subject I want to focus on today, which is to examine some broad themes about where we are in our work and what we can learn from what we have done to shape where we are going. I know that the agenda for the rest of your meeting includes many of my FDA colleagues, who will provide specific information, knowledge, and wisdom about a variety of interests and concerns. Hopefully, you will find that my comments are useful to present some perspective on the overall picture as you continue the amazing work that you are doing.
We are entering a remarkable time in which molecular biology, genetics and genomics, and information technology are converging to open the possibilities for treatment of previously untreatable rare diseases.
As we celebrate this exciting new time, we need to take stock of lessons from the history of therapeutic development and recent experiences with rare diseases so that we optimize the efficiency of the development and evaluation of the plethora of potential treatments in the pipeline. We are excited at FDA about the number of previously untreatable diseases that could be cured or ameliorated, but we are also chastened by the history of unfulfilled promises. Armed with the knowledge of the past, the determination of patients and their advocates, the dedication of scientists and clinicians, and public and industrial funding, we are convinced that we are entering a new era of therapeutics
Despite the remarkable progress, the latest data continue to indicate that the vast majority of drugs entered into early phase human testing will not make it to market. This is due to a complex combination of failure to demonstrate efficacy, unexpected toxicity, and difficulty with manufacturing.
This is hard work that takes remarkable persistence!
Therefore, while speed to access is vital to suffering people, we also must continue to develop and implement methods that “separate the wheat from the chaff”, rapidly discarding therapies that are dangerous or ineffective and speeding along therapies that truly provide clinical benefit. And we believe that all members of the ecosystem, FDA itself, patients and their advocates, industry, academia, practitioners, and health systems all have a vital role to play to optimize the amazing opportunity before us.
I want to focus on some of the key issues that I believe deserve consideration as we move forward.
Accelerating Development and Evaluation
The FDA can assist in development of therapies to treat serious or life-threatening diseases, especially those without meaningful effective therapies, to expedite the process and to provide rapid and frequent feedback so that developers move quickly with greater confidence that errors in development will not be made. The options available to FDA include, among others, accelerated approval.
Accelerated approval allows FDA to allow marketing for life threatening or disabling diseases based on substantial evidence that the therapy changes a biomarker in a direction that is “reasonably likely” to predict clinical benefit. By definition, since this pathway is designated for serious therapies without effective treatments, the biomarkers used for approval have not been validated as surrogate endpoints, so there will often be residual uncertainty about clinical benefit at the time of approval.
Accordingly, the statute allows enormous latitude for FDA to consider the spectrum of evidence about biological plausibility, clinical epidemiology, and fundamental knowledge that could link the biomarker of interest to the possibility of being a valid surrogate. In the end, the FDA must make a judgment about whether the measurement in the biomarker plus associated data and information make it “reasonably likely” that the treatment will have clinical benefit.
One fascinating and critical example of the need to continue to work on the regulatory science issues involved in these pathways is the question of what “reasonably likely” actually means. It is not defined either in statute or guidance. Although scientifically the evaluation of the totality of evidence should lead one to a quantitative or probabilistic estimate, there is no guidance on whether “reasonably likely” means that there is a 50 percent, a 75 percent, or a 95 percent chance that the change in the biomarker will lead to a clinical benefit. This approach necessarily vests a lot of public trust in FDA and emphasizes the clear need for the FDA to employ the very best people, and for its advisory committee system and other feedback mechanisms to enable very high quality scientific exchange. This is one of many reasons why my top priority at FDA has been to continue to develop and support our workforce, including working on the advisory committee system to assure that we get the best advice.
Another important program for the rare disease community is expanded access. While expanded access is not technically an expedited pathway program, it is a way to enable patients to gain access to promising therapies.
Expanded access has been the source of much controversy, but the situation is relatively straightforward. When patients and their doctors believe there is no effective alternative on the market and an experimental agent may be useful, they can request access through a form that has been streamlined so that a doctor with a deep knowledge of the patient can make the request with less than an hour’s work.
FDA approves over 99 percent of such requests, but only after considering whether the patient is eligible for an ongoing clinical trial, as generating knowledge about new drugs is our top priority in the pre-market phase, and combining patient access with new knowledge is an extraordinarily positive contribution to relieving suffering. But when there is no possibility of enrolling in a trial, either because of eligibility criteria or logistics (as when the patient lives far away from the nearest study site and cannot travel), it is up to the company that manufactures the drug to decide whether the drug can be made available.
We are working with the Reagan-Udall Foundation on developing a navigator system to make it even easier to access the system to find the best avenue for the patient. And we are following with interest efforts to increase the transparency of the policies of companies about their experimental drugs and biologics.
Among many reasons to steer expanded access towards appropriate clinical trials, when possible, is the fact that, as I mentioned before, the vast majority of therapies that enter clinical trials – more than 90 percent – have serious toxicity or lack clinical efficacy. So it is critical that we sort out the effective therapies from those that are ineffective or dangerous through high quality clinical trials.
Improving the Quality of Early Studies
The time from academic laboratory to startup and human clinical studies is becoming compressed. NIH grants are leading to discoveries with the potential for rapid translation into treatment, so startup companies can be initiated more quickly and trials started much more quickly than in the past.
It is critical that we see improvements in the quality of these early studies that are typically based in academia, as they will be the basis for regulatory decisions in many situations. Among many other considerations, careful attention to assay validation for biomarkers and the use of randomization early in this process are critical. In studies done purely for academic reasons, there has too often been an assumption that the work is exploratory without great attention to technical details that are important for regulatory decisions
It is difficult to explain the importance of randomization in a short period of time, but we look forward to working with you on the best study designs to figure out which treatments are effective as quickly as possible and randomized comparisons are a critical part of this effort.
And when a regulatory decision is made on a change in a biomarker, it is critical to have confidence that the biomarker can be measured accurately, reliably and can be reproduced in different laboratories – this is what we mean by assay validation.
When studies are done with poor measurements of critical biomarkers or the study is exploratory with no hypotheses, they can not only fail to advance translation toward use of the therapy in practice – we can also end up in a situation in which the results can be misleading, causing inappropriate false hope.
Perhaps less well appreciated is that translational medicine relies on an accumulation of knowledge about a therapy in which the design of new studies is built on knowledge from previous studies – this means that lack of precision and reproducibility in early studies can lead to faulty study design downstream.
We have made numerous advances in conjunction with NIH in this area, including the completion of the final rule for ClinicalTrials.gov, the development of a standard template for protocol design, and the initiation of a joint effort to provide a source of knowledge about biomarkers, the Biomarkers, Endpoints and other Tools (BEsT) Resource.
Clinicaltrials.gov is a major asset to patients and researchers. It was initiated to help patients find clinical trials for consideration of participation, and it has evolved into a critical instrument for transparency. In the final rule that was just released, led by NIH, but also involving major responsibility for FDA, those who conduct clinical trials are now required not only to register that their trials are being done, but also to register their results within one year of completion of the primary endpoint. Importantly, the rule now requires the posting of results for trials, even when therapies do not make it to market, and it requires posting of protocols, including analysis plans.
Trials of failed therapies are especially important to patients with serious and rare diseases so that we all learn about what not to do in therapeutic development. If a treatment doesn’t work we should know it and understand it, so that patients are not exposed to similar therapies under investigation unless there is a good understanding of the key issues and an approach to avoid harm. Moreover, sunshine on both successful and failed protocols should assist all of us in understanding how to design better protocols.
It will be important for patient and research organizations to develop systems to categorize trials, help patients and doctors find the best trials, and use this vital information to plan trials for the future that address the key questions for the field.
Finally, the NIH has extended its commitment to the principles in the final rule to all clinical trials it funds, not just certain trials involving drugs and devices
As you can tell, I’m excited about this final rule because it codifies our commitment to create generalizable knowledge when a volunteer consents to be a participant in a study.
I’ve already discussed the critical importance of improving the conduct of NIH-funded translational studies. We are fortunate to be able to work with the NIH leadership through the Joint Leadership Council, started by my predecessor Peggy Hamburg working with Francis Collins at NIH. We meet on a regular basis to identify issues of common interest and then to deal with them directly.
Through our work on the final rule for Clinicaltrials.gov, as well as many other strategies announced by NIH, we realized that scientists working in the laboratory and doing the critical discovery science work that leads to cures often have little experience with human clinical trials. Through the Joint Leadership Council, we have now developed a protocol design template that we believe will help NIH investigators design studies that meet regulatory standards.
The Biomarker, Endpoints and other Tools (BeST) Resource creates a publicly accessible compendium to provide definitions and context for the tools of drug and device development. For all diseases, and especially for rare diseases, the key to progress is identification of a gene or protein or physiological measurement that is in the causal chain for causing the disease. Easy examples are cholesterol for heart disease or blood sugar, and glucose, for diabetes.
Working with NIH we realized that all too often the science moves forward without full awareness of the implications of assumptions about both biomarkers and clinical endpoints. The BeST resource, representing a consensus between NIH and FDA, and increasingly from the external community, is housed by the National Library of Medicine at NIH and it is publicly available, and helps address this lack of awareness.
Completion of Confirmatory Studies
While accelerated approval and other means of speeding drug development are welcome, their common use points to the need for high quality post-market studies to confirm or refute assumptions made based on less complete data available when approvals are accelerated.
In the long run, we depend on high quality evidence so that patients and their doctors can have confidence that when a treatment is prescribed, it will have a positive balance of risk and benefit.
Once a treatment is on the market, it is hard to think about participating in a trial unless it offers a real chance of therapeutic benefit. Yet, knowing that the majority of therapies that enter the development pipeline are not effective or have dangerous side effects that keep them off the market, creates a mandate that when we approve a drug based on effects on a biomarker or clinical improvement that is not robust, we must follow up with post market studies.
Here I have good news. Coming into the FDA I had the perception that the majority of post-market commitments to conduct definitive trials were not met by the sponsor.
Ongoing work by a team led by Peter Lurie, our associate commissioner for public health strategy and analysis, along with content experts in our Center for Drug Evaluation and Research (CDER), shows that the ecosystem is doing much better than I expected with post-market commitments. And we are making progress in publishing the results. Stay tuned for definitive data on this issue in the near future, but we should aim for 100 percent completion and publication of the results of post-market commitments.
I believe that it is imperative that we continue to work together to understand the importance of definitive evidence, so that as we make progress we can discard less effective treatments in favor of the most effective therapies for every person—the essence of precision medicine. And as we embrace the need for a continuous effort to learn through registries, clinical trials and data analysis, we also work together as a community to understand the best study designs and analytical methods for rare diseases.
Effectively Acting on Findings of Confirmatory Studies
Finally, if such studies do not confirm a positive benefit risk balance in the population intended for treatment, it will be important to assure that the product will either be removed from the market or its label changed to reflect the finding.
We recognize how difficult this can be. A combination of factors leads to this difficulty. Placebo effects and expectations, often driven by publicity and marketing associated with a promising therapy, can have a powerful impact on perceptions, leading to confusion about the true effect of a treatment in an individual.
There is also considerable variability in the natural history of most diseases so that some people who would have done well without the treatment mistakenly attribute their clinical improvement to the drug or device. On the other hand, there is also the possibility that a therapy that is ineffective or dangerous for most people might benefit a few.
All of this leads to reluctance to accept that a treatment may not be effective. I have a deep, visceral understanding of this issue. Having spent a career developing and evaluating therapies, I have worked for years, even decades, on a drug or device, only to find that when the definitive trials are done, the treatment doesn’t work, or that an unanticipated adverse event profile makes it negative from the perspective of the balance of benefit and risk.
Many times I saw research teams and pharmaceutical companies cling to the belief that the treatment was beneficial despite mounting evidence to the contrary.
We must have the courage to evaluate without bias so that we can move on to better treatments when our current choices are suboptimal or ineffective and we can have confidence in celebrating therapeutic successes.
Independence of FDA in Decision-Making
The complex process of drug and device development to provide the evidence needed to make a decision about approval and labeling has a long history replete with precedents and accumulated wisdom. While it is essential for FDA to be collaborative with the community of patients, advocates, academia, and industry during development, one of the most important issues is the preservation of independence of the FDA as a regulatory and public health agency from the vicissitudes of political influence. And for decision-making about market approval and final approval of labeling, external influence should be kept to a minimum.
This was a critical part of my decision to defer to the Center Director about accelerated approval of eteplirsen. Setting a precedent of political appointees intervening in decisions that belong in a scientific process would risk opening the door to a potentially dangerous temptation for others, including political appointees within government and other non-FDA groups to intervene more frequently.
While it is true that FDA decision-making is difficult and imperfect, political meddling would undermine confidence and introduce the type of bias that is not helpful.
In this regard, it is clear that the medical product center, comprised of professionals who are FDA employees and carefully vetted for financial conflicts, should make the decision. An admirable process with strong historical precedent enables the FDA to make decisions that are rational and defensible.
An organized system of appeal allows those who disagree to be heard at higher administrative levels. In the history of FDA regulation of medical products, the politically appointed Commissioner or Secretary of HHS has rarely intervened to override a decision from a medical product center.
I have been pleased to experience great awareness of these issues in this administration as in previous administrations. And I have done my best to continue to support the strong culture of professionalism within FDA—collaborative in generating the evidence, but independent in decision-making.
The record for decision-making when products come on the market is public, but concern for trade secrets and intellectual property has hindered transparency when products do not make it to market. We will continue to carry on work to increase the degree of transparency.
Having said this, constructive analysis and critique from all sectors is a healthy part of FDA decision-making. However, some critics have devolved into name calling and taunting of FDA employees. Such personal attacks on public servants is unseemly and inappropriate.
Interaction with Patient Advocacy Groups
While independence of the FDA in decision-making is a critical issue, interaction of the FDA with the external “ecosystem” is essential for multiple reasons. In general, a more outgoing FDA has been good for the efficient development and assessment of technologies. The more knowledgeable the cadre of FDA reviewers about the disciplinary (clinical medicine, pharmacology, biostatistics, engineering, etc.) and clinical medical (oncology, mental health, cardiology, etc.) fields that support product development, the better the ability to assess the proper design of studies and interpretation of the evidence.
So, it is critical that FDA reviewers participate in the professional meetings where new knowledge that propels the field is shared. For example, many of the reviewers in the Office of Hematology and Oncology Products have joint appointments at NIH. And many FDA reviewers practice clinical medicine part-time.
But no one knows more about the important outcomes of diseases that need to be modified than patients themselves. Indeed, in FDA’s well-developed patient-focused drug development program it has been of interest to realize that at times the endpoints and outcomes considered critical by clinicians are not the same as the priorities of patients. And in the device arena, we are learning a lot about the preferences of patients, which vary considerably in terms of the risk benefit trade-offs that people consider as they evaluate their choices about therapies.
Within the ecosystem, patients and patient advocates are assuming an increasingly prominent role. As the field evolves, the approaches most likely to yield benefit for patients are increasingly becoming clear.
While there is not time today to go into great detail on this topic, I believe we are getting a better sense of how patients and their advocates can be effective as new therapies are developed and older ones are assessed in the context of an evolving therapeutic landscape.
I’ve had the chance to work directly with the development of the role of patient advocates. In the Clinical Research Forum, an organization of academic medical centers, we realized a decade ago that patient advocacy groups were becoming a powerful and useful force in medicine – at the time there were at least 6,000 patient advocacy groups, and academia was largely unaware. Then I met some extraordinary patient advocates in the Clinical Trials Transformation Initiative (CTTI), a public private partnership working on improving the generation of evidence in this country. On the CTTI website one can find a thorough examination of recommended practices for advocacy groups.
I also had the chance to be the Co-Principal Investigator of the Patient Centered Outcomes Research Institute Network (PCORnet). This network is engaged in a fascinating work-in-progress of developing patient powered research networks – going beyond involvement of patients to putting patients in the driver’s seat.
And now I have the pleasure of leading FDA, and I can assure you that the commitment to patient involvement in the system of product development and evaluation is deep and fundamental across the organization.
This leads to something I’ve been thinking about—what are the most effective activities and approaches for patients and patient advocacy groups? And how should the FDA interact with these organizations? Since I have seen the power of patient advocacy, I find myself wanting to help develop best practices.
Think of it this way: how would you like to have a disease with an ineffective advocacy effort, knowing what we know today?
These are some of my beliefs:
• Patients and their advocates should be involved in every phase of development of technologies to diagnose and treat their diseases.
• This includes advocacy for funding and fund raising.
• But it also includes involvement in the design and development of drugs, biologics and devices. The goal should be to develop therapies that solve the problems that limit length and quality of life—and patients and their advocates are best able to articulate these goals.
• In my own area of career expertise—clinical trials and observational clinical studies, patients should be directly involved in the prioritization, design, recruitment, implementation and analysis of clinical studies. When patients are seeking investigators doing relevant trials rather than investigators struggling to find patients, this is a sign that we have made real progress.
• The natural history studies and registries that are being funded by a variety of organizations, including the FDA, can form the basis for an evidence base to make progress. This need for an evidence base does not stop when a drug or device gets on the market—careful post-market studies and measurement of the quality of healthcare delivery can make a huge difference as shown by an increasing number of published studies. Putting a technology on the market is a critical step, but we must have the discipline to understand how to use it well.
• I would also like to point to the power of social media and wearable, personal devices in these interactions and efforts to understand diseases and their treatments. The ability to directly interact with so many people using these technologies is an amazing opportunity – we will need to understand together how to put these new tools to good use in technology development.
• Finally, I would add a social obligation for advocacy groups to share knowledge about best practices with each other. If this becomes a competition for fixed resources, we will all lose. We need to work together to create a rising tide in advocacy that will lift all boats.
Let me give a quick shout out to precision medicine. I know many of you have been involved in this area, because it is the precision of measurement of genes, proteins and biological systems that will provide effective treatments for the people with diseases whom you care about.
We are on the cusp of announcing enrollment in the Precision Medicine Initiative, and I hope you will take up the call and participate, all the while making your voices heard about how to make it better. The more we can do to get the right treatment to the right patient at the right time, the happier we will all be.
Considering the combination of the Precision Medicine Initiative, the Cancer Moonshot, and all that you will be talking about at this meeting, there is real hope for momentous progress towards your dream of a host of effective treatments for rare diseases.
A Strong and Collaborative Future
These are some of the lessons that we can draw from our past successes – and failures – in this area. Supporting and applying the best cutting edge science, focusing on what works, developing the most rigorous evidence through well designed studies, and collaborating in support of unbiased evaluation of promising solutions will benefit all patients, but can have particular resonance for those patients with rare diseases.
At FDA, we are pleased to be a partner in these efforts. We recognize the leadership and hard work of NORD and its members and we are proud to be a partner with you. And while we’re excited about what we’ve already accomplished together, we know there is much more to be done.
I also want to thank NORD for its continuing support of FDA. Your understanding and support of FDA’s unique and essential role has helped ensure that we have the necessary scientific resources, the increased flexibility, and the ability to incentivize the development of products for rare diseases, all of which are critical to our work to support the development of real treatments and cures for patients with rare diseases.
We look forward to continuing to work together with you.