Federal Register, Volume 90 Issue 51 (Tuesday, March 18, 2025)

[Federal Register Volume 90, Number 51 (Tuesday, March 18, 2025)]
[Notices]
[Pages 12534-12539]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2025-04397]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Agency for Healthcare Research and Quality

Supplemental Evidence and Data Request on Improving the
Management of Menopausal Symptoms in Perimenopausal and Early
Postmenopausal Women: A Systematic Review

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

ACTION: Request for Supplemental Evidence and Data Submission.

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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 on Improving the
Management of Menopausal Symptoms in Perimenopausal and Early
Postmenopausal Women: A Systematic Review, which is currently being
conducted by the AHRQ's Evidence-based Practice Centers (EPC) Program.
Access to published and unpublished

[[Page 12535]]

pertinent scientific information will improve the quality of this
review.

DATES: Submission Deadline on or before April 17, 2025.

ADDRESSES:
Email submissions: epc@ahrq.hhs.gov.
Print submissions:
Mailing Address: Center for Evidence and Practice Improvement,
Agency for Healthcare Research and Quality, ATTN: EPC SEADs
Coordinator, 5600 Fishers Lane, Mail Stop 06E53A, Rockville, MD 20857.
Shipping Address (FedEx, UPS, etc.): Center for Evidence and
Practice Improvement, Agency for Healthcare Research and Quality, ATTN:
EPC SEADs Coordinator, 5600 Fishers Lane, Mail Stop 06E77D, Rockville,
MD 20857.

FOR FURTHER INFORMATION CONTACT: Kelly Carper, Telephone: 301-427-1656
or Email: epc@ahrq.hhs.gov.

SUPPLEMENTARY INFORMATION: The Agency for Healthcare Research and
Quality has commissioned the Evidence-based Practice Centers (EPC)
Program to complete a review of the evidence for Improving the
Management of Menopausal Symptoms in Perimenopausal and Early
Postmenopausal Women: A Systematic Review. AHRQ is conducting this
review pursuant to Section 902 of the Public Health Service Act, 42
U.S.C. 299a.
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 Improving the Management of Menopausal Symptoms in
Perimenopausal and Early Postmenopausal Women: A Systematic Review. The
entire research protocol is available online at: https://effectivehealthcare.ahrq.gov/products/menopausal-symptoms/protocol.
This is to notify the public that the EPC Program would find the
following information on Improving the Management of Menopausal
Symptoms in Perimenopausal and Early Postmenopausal Women: A Systematic
Review helpful:
[ssquf] A list of completed studies that your organization has
sponsored for this topic. 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, a summary, including the following elements, if
relevant: 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 topic. In the list, please provide the
ClinicalTrials.gov trial number or, if the trial is not registered, the
protocol for the study including, if relevant, 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 topic and an index outlining the relevant information in each
submitted file.
Your contribution is very beneficial to the Program. Materials
submitted must be publicly available or able to be made public.
Materials that are considered confidential; marketing materials; study
types not included in the review; or information on topics 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
website 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://effectivehealthcare.ahrq.gov/email-updates.
The review will answer the following questions. This information is
provided as background. AHRQ is not requesting that the public provide
answers to these questions.

Key Questions (KQ)

KQ 1: What are the effectiveness, comparative effectiveness, and
harms of treatments for menopausal symptoms in perimenopausal and early
postmenopausal women?
a. Do the effectiveness, comparative effectiveness, and harms of
treatment vary by dose, delivery mode, formulations, or duration of
treatment?
b. Do the effectiveness, comparative effectiveness, and harms of
treatment vary by timing and type of menopause (early, average;
iatrogenic, natural)?
c. Do the effectiveness, comparative effectiveness, and harms of
treatment vary by individual- or system-level factors?
KQ 2: What is the impact of individual- or system-level factors on
the receipt of treatment for perimenopausal and early postmenopausal
women with symptoms?
a. Individual-level factors include but are not limited to
educational attainment, patient engagement in healthcare, lifestyle
factors, comorbidities.
b. System-level factors include but are not limited to provider
bias, access to care, and social determinants of health.

PICOTS (Populations, Interventions, Comparators, Outcomes, Timing, and
Setting)

[[Page 12536]]

Table 1--PICOTS for KQ 1
------------------------------------------------------------------------
Criteria Inclusions Exclusions
------------------------------------------------------------------------
Population.................. Perimenopausal and Studies limited to
early specific
postmenopausal populations such as
women with breast cancer
menopausal symptoms survivors or HIV
(new onset or carriers, women
worsening of with pelvic organ
vasomotor symptoms, prolapse.
genitourinary Studies solely
symptoms of comprising women
menopause, and with existing
other symptoms). disorders (e.g.,
Eligible women are mood, anxiety,
<10 years since sleep disturbances,
menopause for Black sexual or urinary
and Hispanic women dysfunction,
and <5 years for cognitive changes,
other women or are endometriosis,
age <60; Figure 3 fibroids,
offers a decision endometrial
algorithm to hyperplasia,
account for polycystic ovarian
variability in syndrome).
reporting of age
and years since
menopause and
longer duration in
vasomotor symptoms
by race or
ethnicity..
Vasomotor symptoms:.
Hot flashes.........
Night sweats........
Genitourinary
symptoms of
menopause:.
Genital pain
including
vulvodynia/
vestibulodynia/
dyspareunia..
Vulvovaginal
dryness..
Vulvovaginal itching/
irritation/
discomfort..
Urinary pain
including dysuria..
Involuntary urine
loss/urinary
leakage or urinary
frequency..
Skin thinning.......
Pelvic floor
dysfunction..
Other symptoms:.....
Joint pain..........
Mood lability.......
Change in severity
or persistence of
mental health
disorders..
Cognitive changes...
Sleep disturbances..
Subgroups of
interest
(preplanned only):
Natural menopause.
Iatrogenic (e.g.,
surgical)
menopause,
premature
menopause, early
menopause.
Early perimenopausal
women (prior to and
through 1 year from
the final menstrual
period).
Women with/without
hysterectomy.
Women at increased
risk for breast
cancer, women at
increased risk for
heart disease.
Individual- and
system-level
factors (e.g.,
socioeconomic
status, social
determinants of
health, race/
ethnicity).
Intervention \a\............ Systemic hormone Anti-estrogen
therapy (Appendix therapy.
A):. Nonhormonal
FDA-approved hormone treatments such as
therapies: vitamins and herbs.
estrogens alone, Energy-based
estrogens + therapies (e.g.,
progestin, laser).
estrogens + Behavioral therapies
progesterone, (e.g., yoga,
estrogens + dance).
androgen, androgens Nonsystemic
(including therapies.\c\
testosterone),
micronized
progesterone,
synthetic
progestins, tissue-
selective estrogen
complex (e.g., CEE/
bazedoxifene),
compounded
menopausal hormone
therapy (compounded
in 503B outsourcing
facilities),\b\
``bioidentical
hormones''..
Subgroups of
interest
(preplanned only):.
Route of delivery:
oral, transdermal,
pellets (for cBHT),
vaginal,
intramuscular..
Specific nonhormone
therapies:.
paroxetine or
paroxetine mesylate
(common brand
names: Paxil, Paxil
CR, Brisdelle)..
venlafaxine (common
brand names:
Effexor XR)..
desvenlafaxine
(common brand
names: Pristiq)..
escitalopram (common
brand names:
Lexapro).
citalopram (common
brand names:
Celexa).
duloxetine (common
brand names:
Drizalma,
Cymbalta).
sertraline (common
brand names:
Zoloft).
fluoxetine (common
brand names:
Prozac, Symbyax).
gabapentin (common
brand names:
Neurontin, Gralise,
Horizant).
fezolinetant/
neurokinin-3 (NK-3)
receptor antagonist
(common brand
names: Veozah).
elinzanetant/
neurokinin-1,3 (NK-
1,3) receptor
antagonist (common
brand names:
none).\d\

[[Page 12537]]

oxybutynin (common
brand names:
Ditropan, Oxytrol,
Gelnique).
clonidine (common
brand names:
Catapres, Duraclon,
Iopidine, Nexiclon
XR, Onyda XR).
pregabalin (common
brand names:
Lyrica).
Comparator.................. Benefits:........... Same as above.
Placebo or inactive
control, alternate
treatment (i.e.,
any other eligible
intervention)..
Harms:
No treatment,
placebo or inactive
control (e.g.,
vitamins),
alternate treatment
(i.e., any other
eligible
intervention)..
Outcomes \e\................ Benefits:........... Intermediate or
Validated measures nonclinical
of new or worsening outcomes such as
symptoms vaginal pH,
(frequency, arterial intimal
severity, distress/ thickness, fracture
bother) of:. scores.
Vasomotor symptoms..
[cir] Hot flashes...
[cir] Night sweats..
Genitourinary
symptoms of
menopause:
[cir] Genital pain
including
vulvodynia/
vestibulodynia/
dyspareunia.
[cir] Vulvovaginal
dryness.
[cir] Vulvovaginal
itching/irritation/
discomfort.
[cir] Urinary pain
including dysuria.
[cir] Involuntary
urine loss/urinary
leakage or urinary
frequency.
[cir] Skin thinning.
[cir] Pelvic floor
dysfunction.
Other symptoms:
[cir] Joint pain.
[cir] Mood lability.
[cir] Change in
severity or
persistence of
mental health
disorders.
[cir] Cognitive
changes.
[cir] Sleep
disturbances.
Treatment
satisfaction.
Sexual function.
Quality of life.
Harms or health
impact:
Abnormal uterine
bleeding.
Coronary heart
disease.
Stroke.
Venous
thromboembolism.
Breast cancer.
Endometrial cancer.
Colorectal cancer.
Ovarian cancer.
Osteopenia and
osteoporosis.
Alzheimer's disease
and other
dementias, or
cognitive decline.
Side effects of
treatment including
liver damage.
Multimorbidity (2 or
more conditions).
All-cause mortality.
Timing...................... Onset of treatment Later onset of
at or near treatment.
menopause (through Less than 12 weeks
5 years of the duration of
final menstrual treatment.
period [10 years
for Black and
Hispanic women]).
At least 12 weeks
duration of
treatment..
Sample size................. All for benefits.... None for benefits.
>1,000 for harms Cohort studies with
from cohort studies. <=1,000
participants.
Setting..................... Any................. None.
Study design................ Randomized clinical Case series,
trials, controlled narrative reviews,
clinical trials, editorials, and
nonrandomized commentaries;
interventions systematic reviews
(cohorts and case- are not eligible
control studies), but will be
systematic reviews reviewed to
as hand-search determine whether
sources. any included
studies are
eligible.
Years of publication........ 2002 and beyond to Prior to 2002.
ensure relevance to
current clinical
practice.
Language.................... English............. Studies published in
languages other
than English.
------------------------------------------------------------------------
\a\ With the exception of compounded bioidenticals, testosterone, and
hormonal contraceptives, we will limit inclusion to FDA-approved
medications to treat menopausal symptoms. For testosterone and
hormonal contraceptives, we will limit to FDA-approved medications.
\b\ Compounded in a 503A compounding pharmacy, 503B outsourcing
facilities, government healthcare facilities, for academic research,
or for certain studies that were produced to assess off-label outcomes
of FDA-approved products. These facilities are likely to be ``subject
to an increased level of federal oversight, although not as strict as
FDA oversight.'' \20\

[[Page 12538]]

\c\ Local therapies for genitourinary syndrome of menopause have been
previously reviewed by AHRQ.\29\
\d\ Will be included on receipt of FDA approval.
\e\ The proposed list of outcomes integrates core outcome sets defined
for genitourinary syndrome of menopause \30\ and vasomotor
symptoms.\31\
CEE = conjugated equine estrogen; FDA = Food and Drug Administration; KQ
= Key Question; PICOTS = population, intervention, comparators,
outcomes, timing, study design and setting.

Table 2--SPIDER Table for KQ 2
------------------------------------------------------------------------
Criteria Inclusions Exclusions
------------------------------------------------------------------------
Sample...................... Perimenopausal and Studies limited to
early specific
postmenopausal populations such as
women with breast cancer
menopausal symptoms survivors or HIV
(new onset or carriers, women
worsening of with pelvic organ
vasomotor symptoms, prolapse.
genitourinary Studies solely
symptoms of comprising women
menopause, and with existing
other symptoms) or disorders (mood,
their providers. anxiety, sleep
Eligible women are disturbances,
<10 years since sexual or urinary
menopause for Black dysfunction,
and Hispanic women cognitive changes,
and <5 years for endometriosis or
other women or are fibroids,
age <60; Figure 3 endometrial
offers a decision hyperplasia,
algorithm to polycystic ovary
account for syndrome).
variability in Perimenopausal women
reporting of age with menopausal
and years since symptoms in
menopause. countries other
Vasomotor symptoms: than the United
Hot flashes; Night States.
sweats..
Genitourinary
symptoms of
menopause: Genital
pain including
vulvodynia/
vestibulodynia/
dyspareunia;
Vulvovaginal
dryness;
Vulvovaginal
itching/irritation/
discomfort; Urinary
pain including
dysuria;
Involuntary urine
loss/urinary
leakage or urinary
frequency; Skin
thinning; Pelvic
floor dysfunction.
Other symptoms:
Joint pain; Mood
lability; Change in
severity or
persistence of
mental health
disorders;
Cognitive changes;
Sleep disturbances.
Subgroups of
interest
(preplanned only):
Natural menopause;
Iatrogenic (e.g.,
surgical)
menopause,
premature
menopause, early
menopause; Early
perimenopausal
women (prior to and
through 1 year from
the final menstrual
period); Women with/
without
hysterectomy; Women
at increased risk
for breast cancer,
women at increased
risk for heart
disease; Individual-
and system-level
factors (e.g.,
socioeconomic
status, social
determinants of
health, race/
ethnicity).
Phenomenon of interest \a\.. Receipt of systemic Any other phenomenon
hormone therapy: (e.g., shared
FDA-approved decision making).
hormone therapies: Receipt of any other
estrogens alone, therapy.
estrogens +
progestin,
estrogens +
progesterone,
estrogens +
androgen, androgens
(including
testosterone),
micronized
progesterone,
synthetic
progestins, tissue-
selective estrogen
complex (e.g., CEE/
bazedoxifene),
compounded
menopausal hormone
therapy (compounded
in 503B outsourcing
facilities),\b\
``bioidentical
hormones''.
Specific nonhormone
therapies:
paroxetine or
paroxetine mesylate
(common brand
names: Paxil, Paxil
CR, Brisdelle);
venlafaxine (common
brand names:
Effexor XR);
desvenlafaxine
(common brand
names: Pristiq);
escitalopram
(common brand
names: Lexapro);
citalopram (common
brand names:
Celexa); duloxetine
(common brand
names: Drizalma,
Cymbalta);
sertraline (common
brand names:
Zoloft); fluoxetine
(common brand
names: Prozac,
Symbyax);
gabapentin (common
brand names:
Neurontin, Gralise,
Horizant);
fezolinetant/
neurokinin-3 (NK-3)
receptor antagonist
(common brand
names: Veozah);
elinzanetant/
neurokinin-1,3 (NK-
1,3) receptor
antagonist (common
brand names: none);
\c\ oxybutynin
(common brand
names: Ditropan,
Oxytrol, Gelnique);
clonidine (common
brand names:
Catapres, Duraclon,
Iopidine, Nexiclon
XR, Onyda XR);
pregabalin (common
brand names:
Lyrica).
Design...................... No treatment, Same as above.
placebo or inactive
control, alternate
treatment (i.e.,
any other eligible
intervention)
active.
Evaluation.................. Factors explaining Any other evaluation
receipt of (including
treatment (defined evaluation of
as treatment factors upstream
offered by from receipt such
prescriber, as shared decision
treatment received making and access).
by patient, and
treatment initiated/
used/adhered to by
patient).
Years of publication........ 2009 and beyond..... Prior to 2009.

[[Page 12539]]

Research type............... Qualitative, survey, Case studies,
mixed methods, narrative reviews,
original research. editorials, and
commentaries;
systematic reviews
are not eligible
but will be
reviewed to
determine whether
any included
studies are
eligible.
Language.................... English............. Studies published in
languages other
than English.
Geographic setting.......... United States....... Any other country.
------------------------------------------------------------------------
\a\ With the exception of compounded bioidenticals, testosterone, and
hormonal contraceptives, we will limit inclusion to FDA-approved
medications to treat menopausal symptoms. For testosterone and
hormonal contraceptives, we will limit to FDA-approved medications.
\b\ Compounded in a 503A compounding pharmacy, 503B outsourcing
facilities, government healthcare facilities, for academic research,
or for certain studies that were produced to assess off-label outcomes
of FDA-approved products. These facilities are likely to be ``subject
to an increased level of federal oversight, although not as strict as
FDA oversight.'' \20\
\c\ Will be included on receipt of FDA approval.
CEE = conjugated equine estrogen; FDA = Food and Drug Administration; KQ
= Key Question; SPIDER = sample, phenomenon, design, evaluation, and
research.

Dated: March 12, 2025.
Marquita Cullom,
Associate Director.
[FR Doc. 2025-04397 Filed 3-17-25; 8:45 am]
BILLING CODE 4160-90-P