[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: <a href="/cdn-cgi/l/email-protection#b4c7d5c6d59ac7c0c6d5d0d8d1cdf4d2d0d59adcdcc79ad3dbc2"><span class="__cf_email__" data-cfemail="9deefceffcb3eee9effcf9f1f8e4ddfbf9fcb3f5f5eeb3faf2eb">[email protected]</span></a>.

[[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


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