[Federal Register Volume 75, Number 228 (Monday, November 29, 2010)]
[Notices]
[Pages 73104-73106]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-29927]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2010-N-0547]
Clinical Development Programs for Sedation Products; Request for
Assistance
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is seeking information
on a variety of issues related to the clinical development and use of
sedation products in adult and pediatric age groups. FDA is inviting
any interested party, or parties, to facilitate an evaluation of
critical fundamentals of the science related to sedation products by
conducting and managing a coordination of activities that will bring
together experts in the field, including from academia, patient
organizations, and industry. The first step in this process would be
for the party or parties to plan and hold one or more public meetings
to discuss these issues. FDA intends to take into account the
information provided from these activities as we develop FDA guidance
on clinical development programs for sedation products. We intend to
submit to the docket all the information received in response to this
notice so that interested parties may be fully informed.
DATES: Submit electronic or written comments on this notice by January
28, 2011.
ADDRESSES: Submit electronic comments on this notice to http://www.regulations.gov. Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Sara E. Stradley, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, rm. 3162, Silver Spring, MD 20993-0002, 301-
796-1298, FAX:301-796-9713, e-mail: [email protected].
[[Page 73105]]
SUPPLEMENTARY INFORMATION:
I. Background
Because of the need for more information on the development of
products intended to be used in humans for sedation in hospital and
outpatient settings, FDA is requesting assistance from the public in
conducting scientific analyses for the purpose of further understanding
the physiology of sedation and clinical trial design issues related to
the development of sedation products.
II. Request for Assistance
FDA is inviting any interested group or consortium of interested
groups from academia, industry, practitioners, as well as patients and
their representatives to conduct and manage the coordination of a
critical evaluation of certain fundamentals of the science related to
sedation products. Initially, the party or parties would organize and
hold one or more public meetings or workshops to discuss relevant
questions associated with the spectrum of sedation, particularly as it
relates to procedural and intensive care unit (ICU) sedation, as well
as associated clinical trial design issues. FDA believes that a public
meeting would help solicit feedback from all parties leading to
conceptual advances and a discussion of such advances in a concept
paper. This discussion would take into account challenges involved in
assessment of sedation and emphasize the rationale for various
approaches to key clinical trial design issues involving sedation
products. The effort would ultimately lead to developing a draft
guidance that would be issued by FDA for broad public comment before
finalization, consistent with FDA's good guidance practices regulation
(21 CFR 10.115).
III. Suggestions
FDA welcomes other suggestions of activities that could be
undertaken as part of this guidance development effort.
IV. Possible Questions/Issues o Be Considered
To provide a starting point for discussion, FDA has developed a
list of some key concepts that the interested parties may want to
consider for discussion at the meeting as follows:
1. Currently, sedation is studied primarily in the procedural and
ICU settings. Procedural sedation may involve an outpatient setting,
and may require the institution of Monitored Anesthesia Care (MAC).
There is great interest among health care providers with varied medical
backgrounds in sedation for surgical and diagnostic procedures in the
outpatient setting. What generally constitutes MAC, and what qualifies
a product for MAC? How should the need for MAC be assessed in clinical
trials involving sedation products?
2. Assessment of procedural sedation involves conducting clinical
trials in a wide range of diagnostic and surgical procedures. What
surgical and diagnostic procedures are of particular value in assessing
the procedural sedation indication? Are there certain procedures that
should be evaluated for every product that seeks the procedural
sedation indication, or can the range of trials be governed by the
pharmacologic profile of the product? Should the scope of the sedation
guidance apply to settings other than procedural or ICU sedation?
3. There are patient subgroups in which the use of sedation
products should be particularly evaluated. For example, pediatric and
geriatric age groups often require dose adjustment because of varying
metabolic needs and other clinical parameters. In addition, dose
adjustment may be required in patients with renal and hepatic
impairment. Are there other patient subgroups that require specific
evaluation in clinical trials involving sedation products?
4. Sedation products usually are used as infusions that are
titrated to achieve the desired sedation effect. What are optimal trial
designs for sedation products? Should clinical trials involving
sedation products be placebo-controlled or active-controlled?
Currently, Midazolam, Propofol, Ketamine, and Dexmedetomidine are
commonly used sedation products. Of these, Midazolam is the most
commonly used active comparator in sedation product trial designs. Is
it possible to accurately predict the actual size of the treatment
effect based on use of Midazolam or other commonly used sedation
products? Although trial designs involving these products are believed
to be predictive, it may not be possible to generalize from them. If
active- and placebo-controlled product trial designs are not optimal,
what alternative designs can be used to support sedation claims? Would
dose-escalation comparative trial designs be useful in studying
sedation products?
5. How is sedation defined and what are appropriate outcome
measures to assess sedation? At present, there is diverse opinion among
health care providers regarding the definition of sedation. For
example, is the assessment of anxiolysis and agitation a separate
entity or is it contained within the spectrum of sedation itself?
Should this depend upon the known pharmacologic profile of the product?
Currently, the primary efficacy endpoint in sedation clinical trials is
usually assessed using sedation scales. Commonly used sedation scales
include the Ramsey Sedation Scale, Richmond Agitation and Sedation
Scale, and Mean Observer's Assessment of Agitation/Sedation Scale. How
appropriate is the use of such sedation scales in clinical trials
involving sedation products? Should all sedation scales be standardized
and validated?
6. Sedation scales are used for assessing the primary efficacy
endpoint for sedation products. What are meaningful secondary efficacy
endpoints in such trials? Are subjective and objective assessments of
memory, recall, anxiety, agitation, delirium, among others, appropriate
as efficacy endpoints? Which of these efficacy endpoints should be
considered clinically significant? If so, what outcome measures and
trial designs should be used? Specifically, how should anxiolysis and
agitation be assessed within the realm of products primarily indicated
for sedation purposes and not to treat an anxiety disorder or
agitation? Should there be different scales for assessing each
component, or can the assessment be contained within the spectrum of
sedation using an appropriate scale? Further, is an accurate assessment
of anxiolysis feasible given the multiple variables that can affect
anxiety in a procedural sedation setting that would have to be
standardized (e.g., physician and practice setting profile, pre-
procedure anticipatory patient prepping, individual thresholds for
anxiety)?
7. ICU sedation products are often used for periods longer than 24
hours. Should an ICU sedation indication include a short-term (less
than 24 hours) and long-term (more than 24 hours) use assessment for
purposes of efficacy and safety? Long-term use may be associated with
tolerance/tachyphylaxis and a dose-related increase in adverse effects.
What should the size and duration of exposure of the safety database be
for sedation products?
V. Comments
Interested persons should submit comments and expressions of
interest in conducting and managing a critical evaluation to the
Division of Dockets Management (see ADDRESSES). It is only necessary to
send one set of comments. It is no longer necessary to send two copies
of mailed comments. Identify comments with the docket number
[[Page 73106]]
found in brackets in the heading of this document. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday.
Dated: November 17, 2010.
Leslie Kux,
Acting Assisitant Commissioner for Policy.
[FR Doc. 2010-29927 Filed 11-26-10; 8:45 am]
BILLING CODE 4160-01-P