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###### Department of Health and Human Services

###### Food and Drug Administration

          - [Docket No. FDA-2010-N-0547]

# AGENCY:

Food and Drug Administration, HHS.

# ACTION:

Notice.

# 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: sara.stradley@fda.hhs.gov.*

      ( print 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                           ( print 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