[Federal Register Volume 82, Number 26 (Thursday, February 9, 2017)]
[Notices]
[Pages 10015-10018]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-02622]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Agency for Healthcare Research and Quality


Scientific Information Request on Treatment-Resistant Depression: 
A Narrative and Systematic Review of Definitions and Methods in 
Clinical Research Studies

AGENCY: Agency for Healthcare Research and Quality (AHRQ), HHS.

ACTION: Request for Scientific Information Submissions.

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SUMMARY: The Agency for Healthcare Research and Quality (AHRQ) is 
seeking scientific information submissions from the public. Scientific 
information is being solicited to inform our review of Treatment-
Resistant Depression: A Narrative and Systematic Review of Definitions 
and Methods in Clinical Research Studies, which is currently being 
conducted by the AHRQ's Evidence-based Practice Centers (EPC) Program. 
Access to published and unpublished pertinent scientific information 
will improve the quality of this review. AHRQ is conducting this 
systematic review pursuant to Section 902(a) of the Public Health 
Service Act, 42 U.S.C. 299a(a).

DATES: Submission Deadline on or before March 13, 2017.

ADDRESSES: Email submissions: src.org">SEADS@epc-src.org.
    Print submissions:
    Mailing Address: Portland VA Research Foundation, Scientific 
Resource Center, ATTN: Scientific Information Packet Coordinator, P.O. 
Box 69539, Portland, OR 97239.
    Shipping Address (FedEx, UPS, etc.): Portland VA Research 
Foundation, Scientific Resource Center, ATTN: Scientific Information 
Packet Coordinator, 3710 SW U.S. Veterans Hospital Road, Mail Code: R&D 
71, Portland, OR 97239.

FOR FURTHER INFORMATION CONTACT: Ryan McKenna, Telephone: 503-220-8262 
ext. 51723 or Email: src.org">SIPS@epc-src.org.

SUPPLEMENTARY INFORMATION: The Agency for Healthcare Research and 
Quality has commissioned the

[[Page 10016]]

Evidence-based Practice Centers (EPC) Program to complete a review of 
the evidence for Treatment-Resistant Depression: A Narrative and 
Systematic Review of Definitions and Methods in Clinical Research 
Studies.
    The EPC Program is dedicated to identifying as many studies as 
possible that are relevant to the questions for each of its reviews. In 
order to do so, we are supplementing the usual manual and electronic 
database searches of the literature by requesting information from the 
public (e.g., details of studies conducted). We are looking for studies 
that report on Treatment-Resistant Depression: A Narrative and 
Systematic Review of Definitions and Methods in Clinical Research 
Studies, including those that describe adverse events. The entire 
research protocol, including the key questions, is also available 
online at: https://www.ahrq.gov/sites/default/files/wysiwyg/research/findings/ta/topicrefinement/trdepression-protocol.pdf
    This is to notify the public that the EPC Program would find the 
following information on Treatment-Resistant Depression (TRD): A 
Narrative and Systematic Review of Definitions and Methods in Clinical 
Research Studies helpful:
    [ssquf] A list of completed studies that your organization has 
sponsored for this indication. In the list, please indicate whether 
results are available on ClinicalTrials.gov along with the 
ClinicalTrials.gov trial number.
    [ssquf] For completed studies that do not have results on 
ClinicalTrials.gov, please provide a summary, including the following 
elements: Study number, study period, design, methodology, indication 
and diagnosis, proper use instructions, inclusion and exclusion 
criteria, primary and secondary outcomes, baseline characteristics, 
number of patients screened/eligible/enrolled/lost to follow-up/
withdrawn/analyzed, effectiveness/efficacy, and safety results.
    [ssquf] A list of ongoing studies that your organization has 
sponsored for this indication. In the list, please provide the 
ClinicalTrials.gov trial number or, if the trial is not registered, the 
protocol for the study including a study number, the study period, 
design, methodology, indication and diagnosis, proper use instructions, 
inclusion and exclusion criteria, and primary and secondary outcomes.
    [ssquf] Description of whether the above studies constitute all 
Phase II and above clinical trials sponsored by your organization for 
this indication and an index outlining the relevant information in each 
submitted file.
    Your contribution is very beneficial to the EPC Program. The 
contents of all submissions will be made available to the public upon 
request. Materials submitted must be publicly available or can be made 
public. Materials that are considered confidential; marketing 
materials; study types not included in the review; or information on 
indications not included in the review cannot be used by the EPC 
Program. This is a voluntary request for information, and all costs for 
complying with this request must be borne by the submitter.
    The draft of this review will be posted on AHRQ's EPC Program Web 
site and available for public comment for a period of 4 weeks. If you 
would like to be notified when the draft is posted, please sign up for 
the email list at: https://subscriptions.ahrq.gov/accounts/USAHRQ/subscriber/new?topic_id=USAHRQ_18.
    The systematic review will answer the following questions. This 
information is provided as background. AHRQ is not requesting that the 
public provide answers to these questions. The entire research 
protocol, is available online at: https://www.ahrq.gov/sites/default/files/wysiwyg/research/findings/ta/topicrefinement/trdepression-protocol.pdf

The Key Questions

    Narrative Review Questions: Based on a literature search for 
consensus statements, guidelines, materials from the U.S. Food and Drug 
Administration (FDA), the U.S. National Institutes of Health (NIH), and 
the U.S. Substance Abuse and Mental Health Services Administration 
(SAMHSA); systematic reviews; and on a review of UpToDate, an evidence-
based, peer reviewed clinical information source, we will address the 
key questions (Key Questions [KQs] 1 through 5, with their 
subquestions) listed below. In addition, we will use information from 
the Medicare Evidence Development and Coverage Advisory Committee 
(MEDCAC) panel meeting on April 27, 2016, to augment our reporting on 
TRD definitions, study design issues, and the related topics. The 
specific issues are:
    KQ 1. What definitions of TRD are found in this literature? What 
consensus, if any, exists about the best definition(s) for this 
condition?
    KQ 2. What methods do investigators use to diagnose this condition 
in clinical research? What consensus, if any, exists about the best 
measure(s) to use? Does the setting of the medical visit influence the 
choices that investigators make about the diagnostic tool they use?
    KQ 3. What measures have been developed to determine the success 
and failure of treatment in clinical research studies of TRD?

I. What consensus, if any, exists about the best measure(s) to 
investigate treatments for TRD? What are the main points of agreement 
about such measures?
II. Are these measures physician-reported or patient-reported?
III. What are the psychometric properties of these measures? Is the 
minimum significant clinical difference defined for these measures?
IV. Compare and contrast these measures in how they describe:
    A. Change in depression scores as measured by depression scales
    B. Change in depressive symptomatology (e.g., sleep disorders, 
fatigue, weight change, cognition)
    C. Change in measures of anhedonia
    D. Change in measures of functional capacity (e.g., physical 
functioning, ability to care for self)
    E. Change in measures of quality of life
    F. Change in measures of suicide ideation
    G. Change in suicide attempts
    H. Other

    KQ 4. What types of research designs are used to study TRD?

I. What consensus, if any, exists about the type of study design that 
best minimizes bias and the placebo effect in this field?
II. If no consensus exists about study designs to accomplish these 
goals, what are the trends in study designs for assessing interventions 
for TRD? Do these trends reflect long-lasting (e.g., traditional) 
designs or short-lived, evolving, or newly emerging designs?
III. What consensus, if any, exists about the appropriate length of a 
trial?

    KQ 5. What are the risk factors for TRD?
    Systematic Review Questions: From a systematic literature search 
for individual studies on TRD. We will address the KQs 6 through 11 
with their subquestions as listed below.
    KQ 6. What variables were considered for TRD patients in these 
studies? Specify at least the factors listed below.

I. Patient Characteristics:
    A. Age
    B. Type of depressive episode (unipolar, bipolar, psychotic, 
atypical, other)
    C. Number of depression relapses and time to relapse
    D. Psychiatric comorbidities

[[Page 10017]]

    E. Medical comorbidities (e.g., diabetes, cardiac disease, renal 
disease, dementia and other cognitive abnormalities)
    F. Suicidal ideation
    G. Suicide attempts
    H. Duration of symptoms
    I. Screening tools used to make the diagnosis
    J. Diagnostic tools to confirm the diagnosis
II. Prior Treatments:
    A. The number, duration, dosage, or classes of antidepressants 
attempted for each trial of therapy
    B. The number of failed trials of adequate therapy
    C. The number of prior treatment trials that patients did not 
tolerate
    D. The use of augmentation and combination pharmacological 
therapies for each attempted treatment trial
    E. The use of electroconvulsive therapy
    F. The use of psychotherapy
III. Diagnostic characteristics
    A. The use of structured versus unstructured diagnostic assessments
    B. Scores on standardized and validated depression rating 
instruments
    C. Setting in which the diagnosis was made (i.e., primary care, 
generalized psychiatric setting, specialty psychiatric setting, other)

    KQ 7. How do these inclusion criteria compare or contrast with the 
definition(s) of TRD noted in the Narrative Questions?
    KQ 8. What were primary characteristics of included studies?

I. What was the main design of each included study (e.g., randomized 
controlled trial with blinding; interrupted time series; use of 
placebo, wait-list, or sham procedure)?
II. Were run-in or wash-out periods (or both) used in included studies? 
If so, how long were they?
III. How long was each included study?

    KQ 9. How were included studies designed to account for the risk 
factors for TRD (see Narrative Question #5)? If the following 
characteristics are not noted above as risk factors, how did included 
studies account for at least the following: Age, sex, race, 
socioeconomic status, duration of symptoms, disease severity, co-
existing medical and psychiatric conditions, and placebo effect?
    KQ 10. What are relationships between risk factors and various 
results of included studies?

I. Using regression analysis or other statistical techniques, determine 
whether the risk factors for Narrative Review Question #5 and 
Systematic Review Question # 9 can be correlated with study results 
(i.e., the magnitude of treatment effects)?
II. What is the influence of placebo response on the magnitude of 
treatment effects for different types of interventions?
III. Does study duration moderate the influence of placebo response?

    KQ 11. What variables or information did included studies report? 
Specifically:

I. What measures are used to define end points in these TRD trials?
II. In addition to the measures noted for Narrative Review Question #3, 
did these studies record:
    A. Adherence to treatment
    B. Attrition from care
    C. Changes in patient-selected factors of importance (i.e., outcome 
measures identified by patient as important)
    D. Changes in employment or disability status
    E. Changes in use of medical resources (e.g., hospitalizations, 
emergency room or physician visits)
    F. Time to relapse

PICOTS (Populations, Interventions, Comparators, Outcomes, Time Frames, 
Settings)

Population(s)

    All adults (>18 years old) identified as having a depressive 
episode (including major depressive disorder [MDD] and bipolar 
disorder) who have not responded to treatment(s). The depressive 
episode must be part of a major depressive disorder or a bipolar 
disorder. Studies of people without a primary diagnosis of major 
depressive disorder or bipolar disorder, or without evidence of 
treatment nonresponse, will be excluded.

Interventions

    Any pharmacologic intervention tested as a treatment for TRD as a 
primary therapy or as an augmentation agent to an existing primary 
therapy.

I. Antidepressants (e.g., selective serotonin reuptake inhibitors, 
serotonin-norepinephrine reuptake inhibitors, tricyclic 
antidepressants, monoamine oxidase inhibitors atypical agents)
II. Atypical antipsychotics
III. Anticonvulsants
IV. Mood stabilizers
V. Psychostimulants
VI. Agents approved by the FDA for other indications but tested in TRD 
populations (e.g., ketamine, levothyroxine [T3], clonidine)

    Any nonpharmacologic device or procedure tested as a treatment for 
TRD as a primary therapy or as augmentation to an existing primary 
therapy and identified as a TRD option by a consensus statement, 
guideline, the MEDCAC panel, or systematic review (e.g., ECT, 
repetitive transcranial magnetic stimulation, vagus nerve stimulation, 
deep brain stimulation, cranial electrotherapy stimulation).
    Any nonpharmacologic intervention tested as a treatment for TRD as 
a primary therapy or as augmentation to an existing primary therapy and 
identified as a TRD option by a consensus statement, guideline, the 
MEDCAC panel, or systematic review.

I. Complementary and alternative medication therapies
II. Psychotherapy
III. Exercise

Comparators

    All comparative studies with a concurrent control group or a 
control group from an interrupted time-series study. These designs 
exclude pre/post studies that did not conduct interrupted time-series 
analyses.

Outcomes

    Mental health outcomes identified in previous depression 
comparative effectiveness review work as either critical or important 
for decision making:
I. Benefits that are reported as primary endpoints (or outcomes) for a 
trial. Such outcomes could include: Reduction in suicidal ideation or 
suicide attempts
    A. Quality of life
    B. Response to treatment
    C. Remission
    D. Change in depressive severity
    E. Functional capacity (physical and cognitive functioning measured 
by validated scales)
    F. Speed of remission
    G. Speed of response
    H. Intervention durability (rates or counts of recurrence of a 
depressive episode for those who have remitted)
II. Adverse events from the intervention identified as either critical 
or important for decision making. Serious adverse events per FDA 
definition (rates or counts)
    A. Overall adverse events (rates or counts)
    B. Treatment discontinuations attributed to adverse events (rates 
or counts)

Time Frames

I. Any study duration.

[[Page 10018]]

Settings

I. All settings.

    Our population of interest is adults 18 years of age or older with 
depression who have not responded to treatment(s). The depressive 
illness can be part of either major depressive disorder or a bipolar 
disorder, but one of these diagnoses must be a primary diagnosis. For 
example, schizophrenia with a secondary diagnosis of MDD, or dysthymia, 
would not be eligible for this report. If a study involves both 
eligible and ineligible patients and does not report data separately, 
that whole study will be excluded. Populations with no evidence of 
treatment nonresponse (e.g., a study in which the absence of treatment 
response is not part of the selection criteria) will not be eligible.
    Eligible interventions include those that have both been tested as 
a treatment targeting TRD in adults and been identified by guidelines, 
consensus statements, the MEDCAC panel, or systematic reviews as 
alternatives for TRD treatment. These criteria ensure consideration of 
interventions with a minimum threshold amount of data addressing its 
effectiveness in TRD populations. Comparison groups include concurrent 
control groups (e.g., active, sham, or placebo) and a control group 
from an interrupted time series.
    We will require outcomes to have been identified previously as the 
most meaningful to depression management decision making. In our 
earlier comparative effectiveness work on depression, we asked our 
Technical Expert Panel and Key Informants to rank the relative 
importance of these outcomes following a process proposed by the GRADE 
Working Group.30 We used SurveyMonkey(copyright) for an anonymous 
ranking of the relative importance of outcomes. Participants used a 9-
point Likert scale to rank outcomes into three categories: (1) Critical 
for decision making, (2) important but not critical for decision 
making, and (3) of low importance for decision making. They identified 
six outcomes as critical and five as important, and they supported the 
inclusion of an additional depressive outcome (change in depressive 
severity). For one of the adverse events outcomes, serious adverse 
events, we will use the FDA definition and will consider physical, 
psychological, and cognitive events. We will require relevant studies 
for the current project to report on at least 1 of these 12 outcomes.
    All study durations and all settings are eligible. Pre/post studies 
that do not use interrupted time series analyses will be excluded, 
because potential confounding from multiple sources renders 
questionable the ability of these study designs to support causal 
inferences. We will include English-language articles and exclude 
studies that are not published fully in English.

Sharon B. Arnold,
Acting Director.
[FR Doc. 2017-02622 Filed 2-8-17; 8:45 am]
BILLING CODE 4160-90-P