Notice2026-18805
Statistical Considerations for the Design of Rare Disease Clinical Investigations; Establishment of a Public Docket; Request for Information and Comments
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Published
September 15, 2026
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency, or we) is establishing a public docket to collect feedback on statistical considerations for rare disease clinical investigations. This docket is open in conjunction with a Rare disease Innovation, Science, and Exploration (RISE) Workshop on the same topic. Feedback is welcome both on the attached pre-read documents and on the content covered in the Workshop itself.
Full Text
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<title>Federal Register, Volume 91 Issue 177 (Tuesday, September 15, 2026)</title>
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[Federal Register Volume 91, Number 177 (Tuesday, September 15, 2026)]
[Notices]
[Pages 58456-58458]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-18805]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2026-N-10165]
Statistical Considerations for the Design of Rare Disease
Clinical Investigations; Establishment of a Public Docket; Request for
Information and Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; establishment of a public docket; request for
information and comments.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
establishing a public docket to collect feedback on statistical
considerations for rare disease clinical investigations. This docket is
open in conjunction with a Rare disease Innovation, Science, and
Exploration (RISE) Workshop on the same topic. Feedback is welcome both
on the attached pre-read documents and on the content covered in the
Workshop itself.
DATES: Either electronic or written comments on the notice must be
submitted by November 13, 2026.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of November 13, 2026. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
[[Page 58457]]
<bullet> Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
<bullet> For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2026-N-10165 for ``Statistical Considerations for the Design of
Rare Disease Clinical Investigations; Establishment of a Public Docket;
Request for Information and Comments.'' Received comments, those filed
in a timely manner (see ADDRESSES), will be placed in the docket and,
except for those submitted as ``Confidential Submissions,'' publicly
viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Philipa Friedman, Rare Disease
Innovation Hub, <a href="/cdn-cgi/l/email-protection#ec9e88858282839a8d9885838284998eac8a888dc284849fc28b839a"><span class="__cf_email__" data-cfemail="1f6d7b76717170697e6b767071776a7d5f797b7e3177776c31787069">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
The RISE Workshop series, co-convened by the FDA Rare Disease
Innovation Hub and the Duke Margolis Institute for Health Policy,
brings together innovators in drug development, rare disease research,
patient advocacy, and regulatory science to discuss challenges in the
development of medical products for rare diseases that are common to
multiple rare diseases or a class of diseases and for which evolving
science offers innovative solutions. The workshops focus on cross-
cutting or common issues and do not cover specific products under
review by the Agency.
The September 29, 2026, RISE Workshop focuses on statistical
considerations for rare disease clinical investigations. Statistical
considerations affect numerous aspects of drug development, testing,
and review, including clinical trial design and measurement of product
effectiveness. Statistical review for rare disease products can be
particularly complex, and it requires significant attention to the
nuance of the disease state and specific product. Small patient
populations constrain sample sizes, limit statistical power, and
increase the risk of inconclusive results, yet the urgency of patient
need makes timely, reliable evidence critically important. Every
clinical investigation design decision involves trade-offs between
efficiency and reliability, as well as feasibility and rigor. Meeting
this challenge requires both scientific innovation and a shared
commitment to transparency about those trade-offs.
II. Issues for Consideration and Request for Information
FDA is seeking feedback from the public--including rare disease
medical product developers, disease advocates, and researchers--on the
appropriate use of tailored approaches to statistical review of rare
disease medical products. FDA has developed two pre-read documents that
inform the September 29, 2026, RISE Workshop; one document discusses
statistical considerations for clinical trials of rare disease drugs
and biologics, and the other document covers statistical considerations
for clinical studies of rare disease medical devices. FDA welcomes
feedback on either or both of the pre-read documents, as well as
feedback related to the content discussed in the RISE Workshop itself.
The pre-read documents are attached in their entirety, and FDA is
specifically seeking information that addresses the following
discussion questions from the pre-read documents:
For Drugs and Biologics
1. To what extent should we consider adjusting standard success
criteria (e.g., significance thresholds) in a rare disease trial and
how should disease severity, feasibility constraints, and the
availability of corroborating evidence factor into that decision?
2. What would make randomized designs more acceptable and feasible
to patients and sponsors in rare disease settings and what role can
enhanced medical care for participants in the control arm, patient
engagement, and innovative design features play in addressing the
concerns of patients and advocacy communities? Examples may include:
a. Ensuring that participants on the control arm always receive
treatment and care that meets or exceeds the standard of care they
would receive in clinical practice if they did not participate in the
study.
b. Incorporating sequential analyses to ensure that the study stops
as soon as possible if there is convincing evidence of efficacy or
continues if results are promising but not yet sufficient to inform
reliable conclusions.
3. Endpoint selection in rare diseases involves balancing what
matters most to patients, what is statistically feasible, and what
regulators can accept as evidence of benefit. Where does the rare
disease and statistical community see the greatest unmet need in this
space--and what would most help move the field toward endpoints that
are both meaningful to patients and credible to regulators?
4. Which efficiency-enhancing strategies offer the most feasible
and meaningful gains in rare disease studies--and what practical
barriers currently stand in the way of their wider adoption?
For Medical Devices
1. For new Class III devices for small patient populations, what
are important considerations for the premarket-postmarket data shift
specific to products serving small populations?
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What mechanisms (e.g., registries, electronic health records, post-
approval studies) would best support timely, reliable postmarket data
collection? (Note: the pre-read document uses brain-computer interface
(BCI) devices for amyotrophic lateral sclerosis (ALS) as a case
example.)
2. Under what clinical situations and statistical conditions can a
single-arm device study with a performance goal or external control
provide acceptable evidence of reasonable assurance of safety and
effectiveness for devices for small patient populations--and what pre-
specifications are needed to ensure such designs provide reliable and
acceptable evidence? (Note: the pre-read document uses BCI devices for
ALS as a case example.)
3. What design features would make an external data source
appropriate for future pivotal studies in small populations? What
infrastructure should be built proactively and by whom? (Note: the pre-
read document uses BCI devices for ALS as a case example.)
4. What sources of prior information--feasibility studies, natural
history data, international experience, prior device generations--are
most appropriate and credible in small patient populations, and can
hierarchical borrowing and Bayesian adaptive designs meaningfully
improve efficiency and accelerate reliable evidence generation in this
space?
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-18805 Filed 9-14-26; 8:45 am]
BILLING CODE P
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