FDA Revising ‘Draft Guidance’ on Developing Treatments for Rare Diseases

The U.S. Food and Drug Administration (FDA) is updating its 2015 draft guidelines for drug discovery in rare diseases, with new guidance on natural history — how disorders such as spinal muscle atrophy (SMA) run their course if untreated — the choice of “efficacy endpoints” in clinical trials, and how disease biomarkers might be identified and used.

Public comments are being accepted through mid-March regarding the draft, titled “Rare Diseases: Common Issues in Drug Development,” and subtitled “Guidance for Industry.” Released on Jan. 16, the draft guidance aims to help pharmaceutical companies and other sponsors of clinical trials testing medicines and biological products for rare diseases be more efficient and successful in their development programs. This site is expected to accept the posting of comments once the draft is listed on the Federal Registry.

A public meeting is also planned “to obtain patients’ and caregivers’ perspectives on the impacts of rare diseases on daily life” that might help in the development of new treatments and in improving clinical trials. A date and place is yet to be announced.

“The FDA is committed to supporting the development of treatments for patients with rare diseases and has been focused on advancing policies that will help enable these opportunities,” Scott Gottlieb, the agency’s commissioner, said in a release that accompanied the draft guidance.

“The revised draft guidance … discusses select issues commonly encountered in rare disease drug development,” Gottlieb added. “While similar issues often also come up for common diseases, they’re frequently more difficult to address in the context of a rare disease for which there’s often limited medical and scientific knowledge.”

When finalized, the guidance will present the agency’s current thinking on the topic.

Its 24 pages include discussion of issues in evaluating and validating biomarkers as surrogate endpoints (the outcomes a clinical trial measure therapy effectiveness against), non-clinical aspects of evaluating treatment compounds, a new section on the evaluation of safety questions, and additional information on changes to a medicine’s compounds or product manufacturing processes. It was issued by the FDA’s Center for Drug Evaluation and Research (CDER), and its Center for Biologics Evaluation and Research (CBER).

Sections address disease pathophysiology; clinical manifestations and identification, and the use of biomarkers; non-clinical studies; the selection of efficacy endpoints, or a trial’s main goals in terms of patient outcomes; identifying and validating biomarkers, and using biomarkers as surrogate trial endpoints; evidence of effectiveness and safety; pharmaceutical quality considerations; and interactions with the FDA.

There are also revised updates to a section on natural history studies, including a discussion about how such studies might be used to measure a proposed therapy’s benefits, and the need for disease biomarkers.

“The natural history of rare diseases is often poorly understood, and the need for prospectively designed, protocol-driven natural history studies initiated in the earliest drug development cannot be overemphasized,” the draft states.

While natural history studies are not a trial requirement, the agency advises study sponsors to evaluate early the depth and quality of existing studies to determine how well they might apply. Such efforts may run parallel with drug development work, allowing for adjustments in this work, the draft states.

A fuller understanding of rare diseases, it continues, can help sponsors better define patient populations to target and in identifying key disease subtypes. With time, this would foster a better matching of patients to trial goals.

In cases like when a control group may be impractical or unethical, a quality natural history study might even suffice, the draft suggests. Because of the deadly nature of some rare diseases, experts say, it can be difficult to get enough patients for a viable control group — patients who will not be given the investigative treatment, but a placebo, to see how their outcomes compare with those who are treated.

The agency recommends that natural history studies be of sufficient duration, select data elements based on disease features, collect data from a variety of sources, include patients across a wide spectrum of disease severity and phenotypes (observable clinical traits), and use standardized collection methods and medical terminology.

It also encourages making data from natural history studies publicly available to support and promote rare disease drug development.

“Knowledge about a disease’s natural history can inform many aspects of trials,” the draft states in its section on Evidence of Safety and Effectiveness. “From a safety perspective, this includes planning for disease-specific challenges to patient accrual and retention to maximize the size of the premarket safety dataset. Robust natural history data can also help distinguish drug-related adverse effects from underlying disease manifestation.”

Under Gottlieb’s direction, the FDA appears open to working with patient advocacy groups in crafting rare-disease trials that use more meaningful endpoints and real-world information, instead of depending on placebo groups for efficacy assessments.

Advocacy groups are doing their part. Parent Project Muscular Dystrophy (PPMD) recently released a report outlining key results from its decade-old Duchenne Registry, a collection of data on 4,000 registered Duchenne and Becker muscular dystrophy patients.

“Starting a registry really creates this environment of understanding data, and the willingness to apply known medical tools to improve patients’ quality of life while treatments are being developed,” Pat Furlong, PPMD’s president and chief executive officer, said in a 2018 interview. “As these tools are applied and people use ventilation and steroids, all this is evolving the natural history of the disease, so they’re living longer and more quality lives.”

Information gathered from 2005 to 2016 in the Cooperative International Neuromuscular Research Group (CINRG)’s Duchenne Natural History Study (DNHS) — a comprehensive study of Duchenne clinical outcomes and disease progression — has also shaped the way scientists and healthcare professionals see the natural course of disease, and serves as a guide for current and future research. New enrollment on an expanded study began last year.

Based in Europe, the TREAT-NMD Neuromuscular Network also established an international registry for patients with Duchenne. The registry collects data from national registries worldwide.

In collaboration with private rare disease foundation Rettsydrome.org and other patient advocacy groups, the National Institutes of Health (NIH) National Center for Advancing Translational Science (NCATS) Rare Diseases Clinical Research Network (RDCRN) funded the development of a consortium in 2014 to study the natural history of Rett syndrome and related disorders. The study runs through this year.

Similar efforts underway into rare diseases include:

• A data registry run by Cystic Fibrosis Foundation (CFF) since 1986. Of note, therapies are advancing in this disease to the point where it may be difficult to perform certain trials with protracted placebo periods.
• SMA patient registries, including an international registry supported by Cure SMA, the SMA Foundation, and other patient advocacy groups.
• Work of the natural history of infantile SMA that seeks to define and help set natural progression and disease biomarkers as endpoints in clinical trials. It is  conducted by the National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT).
• A Sanofi-Genzyme patient registry for Fabry disease that opened in 2001 and runs through 2021.
• Services grouped under the Registry Program run by National Organization for Rare Disorders (NORD), created to guide its many member groups through all steps of developing, launching, and running a registry. The NORD Natural History Study Database Project is part of this project.

The FDA in 2017 awarded research grants totaling $6.3 million for natural history studies in rare diseases, the first time the agency provided funding for such purpose through its Orphan Products Grants Program.

“Many of the updates are in direct response to feedback that we received on our prior draft,” Gottlieb said in the FDA release. “By continuing to provide clarity and direction to drug developers, we hope to help facilitate the development and approval of more safe and effective treatments for patients with rare diseases.”