Talking with Billy Dunn, M.D., who is the director of the Division of Neurology Products in CDER’s Office of New Drugs.
FDA recently published five guidances for industry related to neurological conditions. The release of these guidances was noteworthy for many reasons and reflects a renewed commitment to describing the agency’s thinking and providing advice on conducting clinical studies in specific neurological indications. Billy Dunn, who is the director of CDER’s Division of Neurology Products, discusses the guidances and why they are significant.
What are the guidances that were recently issued?
Overall, five guidances were released. Two of the guidances are final versions. These are:
- Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment
- Migraine: Developing Drugs for Acute Treatment
Three are draft versions. These are:
- Early Alzheimer’s Disease: Developing Drugs for Treatment
- Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment
- Drugs for Treatment of Partial Onset Seizures: Full Extrapolation of Efficacy from Adults to Pediatric Patients 4 Years of Age and Older
In a broad sense, what makes these new guidances noteworthy?
For many years, neurological diseases have been poorly understood. Recently, we have been witnessing an explosion of new scientific knowledge about the nervous system. We know that many drug developers in neurology are working in focused areas, and they are looking for clear paths to treatment solutions. We recognize that there is a need for timely advice that can help advance a more efficient scientific and drug development process.
These five documents, which are the result of an enormous amount of work by many people at FDA, are part of a push to develop more disease- or indication-specific guidances. We believe that organizing them by disease is most useful to our key stakeholders. We worked with many patient advocacy organizations and scientists to ensure that their voices were heard and their ideas were incorporated. We may not be able to write a guidance for every neurological disease—there are hundreds — but we are focusing on providing advice where we can be most useful, and these guidances are good examples of that. These guidances also benefited from a streamlined internal review process that encourages the development of short, concise documents free of unnecessary background information.
How do you expect these guidances to be received by the stakeholder community?
We are highly engaged with the Alzheimer’s disease (AD), Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), migraine, and epilepsy communities, along with many others. Our guidance development is informed by and benefits from our involvement in these areas. Moreover, we have had frequent conversations with multiple drug developers about their needs, and these guidances incorporate much of their input, as well.
Let’s look at each of the guidances individually. What is noteworthy about:
…the final DMD guidance?
This final version of the guidance is a good example of the involvement of the stakeholder community. An enormous amount of research in DMD is underway, and it is leading to a better understanding of the fundamentals of the disease and of the underlying gene mutations. A leading DMD stakeholder, Parent Project Muscular Dystrophy, developed and submitted its own comprehensive guidance document on DMD in 2015. To our knowledge, this was the first time our guidance was preceded by an advocacy group’s proposed guidance. It is an excellent resource on its own and helped inform our own efforts. We continue to work with all DMD stakeholders to further drug development for DMD.
…the final migraine guidance?
Migraine is a common condition. One of the leading causes of disability and lost productivity, migraine affects 30 million Americans. This new guidance is the culmination of many conversations with the scientific and patient advocacy communities. Spearheaded by Eric Bastings, M.D., who is the deputy director of the neurology division, the guidance provides drug developers with advice on how to conduct the most efficient trials for the acute treatment of migraine attacks. Traditionally, drug companies had to look at four different endpoints to determine efficacy. This new guidance states that they need only consider two primary endpoints when designing studies —1) pain, and 2) the most disabling symptom as reported by the patient, such as nausea, light sensitivity, or sound sensitivity. This innovative new standard recognizes that patients may have different ideas of what is most disabling, and allows clinical studies to be tailored to the individual patient’s experience.
…the draft early AD guidance?
This revised draft guidance reflects the evolution of our thinking since our first draft was released in 2013. Historically, most clinical studies for AD have targeted later stages of the disease, in part because it was in these stages that it was felt an effect could be most reasonably demonstrated. It can be challenging to conduct clinical studies and evaluate patients in the early stages of the disease when symptoms are less pronounced or have not yet emerged. We engaged with a variety of organizations and participated in many different discussions with those in the field and those impacted by the disease. We saw an opportunity to clarify strategies for conducting clinical studies in the early stages of the disease, potentially impacting or even fundamentally changing the course of the disease even before symptoms emerge.
…the draft ALS guidance?
Last year, we approved a new drug for ALS, but additional treatment options are needed for this devastating disease. We have been working closely with the stakeholder community to address the issue. We heard directly from the ALS community at a 2013 public hearing at FDA. Following this hearing, and many other interactions with FDA, the ALS Association developed its own proposed draft guidance, reflecting the broad input of the ALS community. This comprehensive document tackled almost all aspects of ALS and its treatment options, and provided important information about the disease and its impacts on patients. Our draft guidance describes our thinking on drug development for ALS, and exists in conjunction with the ALS community-developed guidance document.
We also have a plan in place for mutually sharing feedback. An upcoming workshop to be hosted by the ALS Association will provide an opportunity for discussion of the two complementary guidance documents.
…the draft pediatric extrapolation in partial onset seizures guidance?
For many conditions, clinical studies can be difficult to conduct in children for multiple reasons, so drug development for pediatric populations can lag. For some indications, we have provided incentives for developers to consider pediatric populations and conduct the necessary studies. In other cases, however, we have been looking for ways to provide the information necessary to support the use of a drug in children without the need for independent pediatric trials.
Examining existing studies, we used a sophisticated approach to confidently determine that if a drug that treats partial onset seizures is shown to work in adults, we can be confident that appropriate dosages of the drug will work in children, as well. This approach, called extrapolation, can replace clinical trials that would otherwise be necessary to establish effectiveness in children, allowing needed seizure treatments to more rapidly get to the children who need them.
We worked with the scientific and patient advocacy communities, as well as our colleagues in CDER’s Office of Clinical Pharmacology, to create this new approach. We are already seeing an effect—two seizure drugs have been approved for use in children on the basis of this new approach, and there are others in the pipeline.
The neurology division is committed to continuing our engagement with stakeholders because we all share the same objective to get these needed therapies to market in the most efficient way. We appreciate the input of the various patient communities and their own efforts in developing complementary, comprehensive documents that exist in conjunction with the agency’s guidances.
The publication of these five guidances follows the finalization of our guidance titled, Evaluating Drug Effects on the Ability to Operate a Motor Vehicle, which was published in late 2017. We plan to continue to develop additional guidances on other neurological topics.
For more information
Read the Statement from FDA Commissioner Scott Gottlieb, M.D. on advancing the development of novel treatments for neurological conditions; part of broader effort on modernizing FDA’s new drug review programs.