Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Study of Disclosures to Healthcare Providers Regarding Data That Do Not Support Unapproved Use of an Approved Prescription Drug, 31318-31323 [2021-12265]
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specific process outlined in the draft
guidance, but rather addressed support
for, or concerns with, the underlying
policy of judicious use of medically
important antimicrobials in animals,
specifically the principle of limiting
medically important antimicrobial drugs
to uses in animals that include
veterinary oversight or consultation. As
described in FDA GFI #209, ‘‘The
Judicious Use of Medically Important
Antimicrobial Drugs in Food-Producing
Animals’’ (77 FR 22328, April 13, 2012),
the development of resistance to this
important class of drugs, and the
resulting loss of their effectiveness as
antimicrobial therapies, poses a serious
public health threat. Developing
strategies to reduce antimicrobial
resistance is critically important for
protecting both public and animal
health. This guidance is an extension of
FDA’s ongoing efforts to promote the
appropriate or judicious use of
medically important antimicrobial drugs
in animals.
This guidance provides information to
sponsors of new animal drug products
containing antimicrobials of human
medical importance who are interested
in changing the approved marketing
status of these products from OTC to Rx
with specific recommendations on
submission of revised labeling. Such
changes are consistent with FDA’s
recommendation that the use of such
antimicrobial drugs in animals include
veterinary oversight in order to mitigate
development of antimicrobial resistance
and thereby preserve the effectiveness of
these drugs for use as therapies to treat
infections in humans and animals. The
guidance also identifies timelines for
stakeholders wishing to comply
voluntarily with this guidance; these
timelines remain as outlined in the draft
guidance. In the final guidance, editorial
changes were made to improve clarity.
This level 1 guidance is being issued
consistent with FDA’s good guidance
practices regulation (21 CFR 10.115).
The guidance represents the current
thinking of FDA on recommendations
for drug sponsors for voluntarily
bringing under veterinary oversight all
medically important antimicrobial drugs
approved for use in animals that
continue to be available as OTC
products. It does not establish any rights
for any person and is not binding on
FDA or the public. You can use an
alternative approach if it satisfies the
requirements of the applicable statutes
and regulations.
II. Paperwork Reduction Act of 1995
While this guidance contains no
collection of information, it does refer to
previously approved FDA collections of
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information. Therefore, clearance by the
Office of Management and Budget
(OMB) under the Paperwork Reduction
Act of 1995 (PRA) (44 U.S.C. 3501–
3521) is not required for this guidance.
The previously approved collections of
information are subject to review by
OMB under the PRA. The collections of
information in section 512(n)(1) of the
Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 360b(n)(1)) have been
approved under OMB control number
0910–0669; the collections of
information in 21 CFR part 514 have
been approved under OMB control
number 0910–0032.
III. Electronic Access
Persons with access to the internet
may obtain the guidance at either
https://www.fda.gov/animal-veterinary/
guidance-regulations/guidance-industry
or https://www.regulations.gov.
Dated: June 7, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for
Policy.
[FR Doc. 2021–12297 Filed 6–10–21; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
02761, in the first column, the first two
paragraphs under the section ‘‘II.
Determination of Regulatory Review
Period,’’ the following correction is
made on page 6034:
FDA has determined that the
applicable regulatory review period for
BRAVECTO is 1,054 days. Of this time,
1,016 days occurred during the testing
phase of the regulatory review period,
while 38 days occurred during the
approval phase. These periods of time
were derived from the following dates:
1. The date an exemption under
section 512(j) of the FD&C Act (21
U.S.C. 360b(j)) became effective: June
28, 2011. The applicant claims February
19, 2010, as the date the investigational
new animal drug application (INAD)
became effective. However, after
consideration of additional information
presented by the applicant in response
to the Federal Register notice (83 FR
6033), FDA has determined that the start
of the testing phase was June 28, 2011,
which was the date the first major
health or environmental effects test
began.
Dated: June 3, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for
Policy.
[FR Doc. 2021–12284 Filed 6–10–21; 8:45 am]
BILLING CODE 4164–01–P
[Docket No. FDA–2015–E–2079]
Determination of Regulatory Review
Period for Purposes of Patent
Extension; BRAVECTO; Correction
AGENCY:
[Docket No. FDA–2020–N–1261]
Notice; correction.
The Food and Drug
Administration (FDA or Agency)
published a notice in the Federal
Register of February 12, 2018. After
review of a timely request for
reconsideration by the applicant of the
determination of the regulatory review
period of the animal drug, BRAVECTO,
in that notice, FDA has determined that
a revision of the SUPPLEMENTARY
INFORMATION section is warranted. This
document presents the revised
regulatory review period.
FOR FURTHER INFORMATION CONTACT:
Beverly Friedman, Office of Regulatory
Policy, Food and Drug Administration,
10903 New Hampshire Ave., Bldg. 51,
Rm. 6250, Silver Spring, MD 20993,
301–796–3600.
SUPPLEMENTARY INFORMATION:
SUMMARY:
Correction
In the Federal Register of February
12, 2018 (83 FR 6033), in FR Doc. 2018–
PO 00000
Food and Drug Administration
Food and Drug Administration,
HHS.
ACTION:
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
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Agency Information Collection
Activities; Submission for Office of
Management and Budget Review;
Comment Request; Study of
Disclosures to Healthcare Providers
Regarding Data That Do Not Support
Unapproved Use of an Approved
Prescription Drug
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA, Agency, or we) is
announcing that a proposed collection
of information has been submitted to the
Office of Management and Budget
(OMB) for review and clearance under
the Paperwork Reduction Act of 1995
(PRA).
SUMMARY:
Submit written comments
(including recommendations) on the
collection of information by July 12,
2021.
DATES:
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To ensure that comments on
the information collection are received,
OMB recommends that written
comments be submitted to https://
www.reginfo.gov/public/do/PRAMain.
Find this particular information
collection by selecting ‘‘Currently under
Review—Open for Public Comments’’ or
by using the search function. The title
of this information collection is ‘‘Study
of Disclosures to Healthcare Providers
Regarding Data That Do Not Support
Unapproved Use of an Approved
Prescription Drug.’’ Also include the
FDA docket number found in brackets
in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Ila
S. Mizrachi, Office of Operations, Food
and Drug Administration, Three White
Flint North, 10A–12M, 11601
Landsdown St., North Bethesda, MD
20852, 301–796–7726, PRAStaff@
fda.hhs.gov.
SUPPLEMENTARY INFORMATION: In
compliance with 44 U.S.C. 3507, FDA
has submitted the following proposed
collection of information to OMB for
review and clearance.
ADDRESSES:
Study of Disclosures to Healthcare
Providers Regarding Data That Do Not
Support Unapproved Use of an
Approved Prescription Drug
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OMB Control Number 0910–New
I. Background
Section 1701(a)(4) of the Public
Health Service Act (42 U.S.C.
300u(a)(4)) authorizes FDA to conduct
research relating to health information.
Section 1003(d)(2)(C) of the Federal
Food, Drug, and Cosmetic Act (FD&C
Act) (21 U.S.C. 393(d)(2)(C)) authorizes
FDA to conduct research relating to
drugs and other FDA-regulated products
in carrying out the provisions of the
FD&C Act.
The Office of Prescription Drug
Promotion’s (OPDP’s) mission is to
protect the public health by helping to
ensure that prescription drug promotion
is truthful, balanced, and accurately
communicated. OPDP’s research
program provides scientific evidence to
help ensure that our policies related to
prescription drug promotion will have
the greatest benefit to public health.
Toward that end, we have consistently
conducted research to evaluate the
aspects of prescription drug promotion
that are most central to our mission. Our
research focuses in particular on three
main topic areas: Advertising features,
including content and format; target
populations; and research quality.
Through the evaluation of advertising
features, we assess how elements such
as graphics, format, and disease and
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product characteristics impact the
communication and understanding of
prescription drug risks and benefits;
focusing on target populations allows us
to evaluate how understanding of
prescription drug risks and benefits may
vary as a function of audience; and our
focus on research quality aims at
maximizing the quality of our research
data through analytical methodology
development and investigation of
sampling and response issues. This
study will inform the first two topic
areas: Advertising features and target
populations.
Because we recognize that the
strength of data and the confidence in
the robust nature of the findings is
improved by utilizing the results of
multiple converging studies, we
continue to develop evidence to inform
our thinking. We evaluate the results
from our studies within the broader
context of research and findings from
other sources, and this larger body of
knowledge collectively informs our
policies as well as our research program.
Our research is documented on our
homepage, which can be found at:
https://www.fda.gov/aboutfda/
centersoffices/
officeofmedicalproductsandtobacco/
cder/ucm090276.htm. The website
includes links to the latest Federal
Register notices and peer-reviewed
publications produced by our office.
The website maintains information on
studies we have conducted, dating back
to a survey on direct-to-consumer
advertisements conducted in 1999.
The revised draft guidance entitled
‘‘Distributing Scientific and Medical
Publications on Unapproved New
Uses—Recommended Practices’’ (2014;
Ref. 1),1 recommends that scientific and
medical journal articles that discuss
unapproved uses of approved drug
products be disseminated with a
representative publication that reaches
contrary or different conclusions, when
such information exists. Similarly, the
draft guidance entitled ‘‘Responding to
Unsolicited Requests for Off-Label
Information About Prescription Drugs
and Medical Devices’’ (2011; Ref. 2) 1
recommends that when conclusions of
articles or texts that are disseminated in
response to an unsolicited request have
been specifically called into question by
other articles or texts, a firm should
disseminate representative publications
that reach contrary or different
conclusions regarding the use at issue.
Pharmaceutical firms sometimes
choose to disseminate publications to
healthcare providers (HCPs) that
1 When final, this guidance will represent the
FDA’s current thinking on this topic.
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include data that appear to support an
unapproved use of an approved
product. At the same time, published
data that are not supportive of that
unapproved use may also exist. For
example, unsupportive published
information could describe an increased
risk of negative outcomes (e.g., death,
relapse) from the unapproved use of the
approved product, suggesting that the
unapproved use does not have a
positive benefit-risk ratio. The purpose
of this research is to examine
physicians’ perceptions and behavioral
intentions about an unapproved new
use of an approved prescription drug
when made aware of other data that are
not supportive of the unapproved use.
This research will also evaluate the
effectiveness of various disclosure
approaches for communicating the
unsupportive information. We will use
the results of this research to better
understand: (1) Physicians’ perceptions
of an unapproved use of a prescription
drug; (2) physicians’ perceptions about
an unapproved use of an approved
prescription drug when they are aware
of the existence of unsupportive
information about it; (3) physicians’
perceptions of disclosures referencing
the existence of unsupportive
information about that particular use;
and (4) to examine the utility and
effectiveness of various approaches to
the communication of this information.
In particular, we plan to examine how
different approaches to the
communication of unsupportive
information affect physicians’ thoughts
and attitudes about the unapproved use.
Five approaches will be examined: (1)
The provision of the unsupportive data
in the form of a representative
publication; (2) a disclosure that
summarizes, rather than provides, the
unsupportive data and includes a
citation to the representative
publication; (3) a disclosure that does
not provide or include a summary of the
unsupportive data but does
acknowledge that unsupportive data
exist and includes a citation to the
representative publication; (4) a general
disclosure that does not provide or
include a summary of the unsupportive
data but acknowledges unsupportive
data may exist, without conceding that
such data do exist; or (5) nothing—the
absence of any presentation of
unsupportive data or any disclosure
about such data (control condition). We
have four research questions:
RQ1: When considering a
presentation of data about an
unapproved use of an approved drug
product, how does the existence of
unsupportive data impact physicians’
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perceptions and intentions with regard
to that unapproved use?
RQ2: How does the way in which the
existence of unsupportive data is
communicated, when the specific data
is not presented, impact physicians’
perceptions and intentions with regard
to an unapproved use of an approved
drug product?
RQ3: How are physicians’ perceptions
of and intentions toward an unapproved
use of an approved drug product
affected by the disclosure of specific
unsupportive data versus disclosure
statements about data that is not
presented?
RQ4: Do other variables (e.g.,
demographics) have an impact on these
effects? These research questions will be
examined in two medical conditions.
We plan to conduct one pretest with
180 voluntary adult participants and
one main study with 1,600 voluntary
adult participants. Participants in the
main study will be 510 oncologists in
the oncology medical condition and
1,090 primary care physicians in the
insomnia 2 medical condition. All
participants will be physicians who
engage in patient care at least 50 percent
of the time and do not work for a
pharmaceutical company, marketing
firm, or the Department of Health and
Human Services. The gender, race/
ethnicity, and ages of the participating
physicians will be self-identified by
participants. We will aim to include a
mix of demographic segments to ensure
a diversity of viewpoints and
backgrounds. Power analyses were
conducted to ensure adequate sample
sizes to detect small to medium effects.
The studies will be conducted online.
The pretest and main studies will have
the same design and will follow the
same procedure. The base stimulus in
both the pretest and main studies will
consist of a sample publication
supporting an unapproved use of an
approved drug product. Within each
medical condition, participants will be
randomly assigned to one of five test
conditions (see figure 1). Following
exposure to the stimuli, they will be
asked to complete a questionnaire that
assesses comprehension, perceptions,
prescribing intentions, and
demographics. In the pretest,
participants will also answer questions
about the study design and
questionnaire.
FIGURE 1—STUDY DESIGN
Accompanied by
disclosure with
summary of
unsupportive data
and including a
citation for that data
Accompanied by
representative
publication with
unsupportive data
Accompanied by
disclosure that
unsupportive data
exist and including a
citation for that data,
but without a
summary of the
unsupportive data
Accompanied by
general disclosure
that unsupportive
data may exist and
no citation
No disclosure or
material about
unsupportive data
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Medical Condition 1
Medical Condition 2
In the Federal Register of July 6, 2020
(85 FR 40300), FDA published a 60-day
notice requesting public comment on
the proposed collection of information.
FDA received two submissions that
were PRA-related. Within these
submissions FDA received multiple
comments that the Agency has
addressed below. For brevity, some
public comments are paraphrased and,
therefore, may not include the exact
language used by the commenter. We
assure commenters that the entirety of
their comments was considered even if
not fully captured by our paraphrasing
in this document. The following
acronyms are used here: HCP =
healthcare provider; FDA and ‘‘The
Agency’’ = Food and Drug
Administration; OPDP = FDA’s Office of
Prescription Drug Promotion.
(Comment 1) One comment asserted
that FDA has not made the stimuli
available for public comment and
requested FDA publish a new 60-day
notice after these comments have been
addressed to give the public another
opportunity to review and comment.
(Response 1) We have provided the
purpose of the study, the design, the
population of interest, and the
questionnaire to individuals upon
request. These materials have proven
sufficient for public comment and for
academic experts to peer review the
study successfully. Our full stimuli are
under development during the PRA
process. We do not make draft stimuli
public during this time because of
concerns that this may contaminate our
participant pool and compromise the
research.
(Comment 2) One comment suggested
that due to the task of reading the
‘‘scientific publication’’ stimuli and
length of the questionnaire, FDA’s
estimation of the time it will take to
complete the study is too low, and thus
the burden of the information collection
is inaccurate.
(Response 2) The scientific
‘‘publications’’ in this study are each
formatted as a one-page brief report. The
text is presented in two columns and
has the following headings:
Introduction, Methods, Results,
Discussion, and Limitations. The survey
contains primarily closed-ended
questions with Likert scales, and there
are five open-ended questions. The
expected time for the study is based on
our prior experience conducting studies
using similar protocols. We will also
test the time during the pretest to ensure
we stay within 20 minutes. If we
determine the average time for
completing the survey is greater than 20
minutes, we will revise the survey prior
to fielding the main study.
(Comment 3) One comment asserts
this proposed study overlaps with other
OPDP research currently in progress and
references several studies.
(Response 3) OPDP may conduct
concurrent or overlapping studies on
similar topics. While the studies
referenced by the comment contribute to
the evidence base for prescription drug
promotion, prior studies had a different
focus than the current study. Prior
disclosure studies examined the
effectiveness of disclosures in
increasing understanding of efficacy
claims (‘‘Disclosures in Professional and
Consumer Prescription Drug
Promotion’’) and the role of disclosures
in mitigating potentially misleading
presentations of preliminary or
descriptive data about oncology drugs
(‘‘Disclosures of Descriptive
2 This medical condition was changed from
diabetes to insomnia based on cognitive testing.
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Presentations in Professional Oncology
Prescription Drug Promotion’’). The
third study mentioned by the comment
(‘‘Physician Interpretation of
Information About Prescription Drugs in
Scientific Publications vs. Promotional
Pieces’’) investigates how physician
perception of professional prescription
drug communications is influenced by
variations in information context,
methodologic rigor of the clinical study,
and time pressure.
The current study uses an
experimental design to compare various
disclosure approaches for
communicating unsupportive
information about an unapproved new
use. The findings of this study will help
inform FDA’s understanding about
when disclosures about unsupportive
data might be useful and what types of
information should be included.
(Comment 4) One comment expressed
concern that the way in which the
proposed research is described in the
notice suggests that pharmaceutical
firms disseminate supportive data but
do not adequately disclose unsupportive
data and that this ‘‘implied bias’’ may
taint the collection and interpretation of
the data.
(Response 4) The sentences referred to
in this comment appear in the Federal
Register notices for the study to provide
background and do not suggest that any
firms are not following the
recommendations in the two guidance
documents referenced in that same
background section. Rather, the
background outlines the current FDA
recommendations around disclosure of
unsupportive data with these types of
communications and the intent of the
study to evaluate alternative approaches
to the disclosure of unsupportive data.
These background statements are not
part of the materials that will be
provided to study participants. Rather,
study instructions tell participants only
that they will be reviewing
informational material about a
prescription drug. No instructional
materials provided to participants
mention a pharmaceutical
manufacturer. Therefore, we do not
believe the collection and interpretation
of study findings will be tainted or
biased.
(Comment 5) One comment suggested
deleting or amending all questions
about HCPs’ prescribing decisions
(Questions 4, 5, 10, 11, 14 to 23) because
these decisions are likely to be
influenced by many factors and are
outside of FDA’s jurisdiction. This
comment also asserted Question 10 is
biased and worded to suggest that
pharmaceutical firms disseminate
supportive data but do not adequately
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disclose unsupportive data and suggests
deleting or amending the question.
(Response 5) As explained earlier, the
Public Health Service Act authorizes
FDA to conduct research relating to
health information, and the FD&C Act
authorizes FDA to conduct research
relating to drugs and other FDAregulated products in carrying out the
provisions of the FD&C Act. The
purpose of the current experimental
study is to examine physicians’
perceptions and behavioral intentions
about an unapproved new use of an
approved prescription drug when made
aware of other data that are not
supportive of the unapproved use and to
evaluate the effectiveness of various
disclosure approaches for
communicating the unsupportive
information. The study is within FDA’s
authority, and it will help to inform
OPDP’s work to help ensure that
prescription drug information is
truthful, balanced, and accurately
communicated so that HCPs and
consumers can make informed
decisions.
Questions 4 and 5 were intended to
assess the impact of various disclosure
manipulations on hypothetical
prescribing decisions. Measuring
behavioral intention is a common
method of assessing knowledge and
attitudes. There is substantial
theoretical and empirical support for
our approach, and strong behavioral
intention has been shown to be
predictive across a wide range of
behaviors, including prescribing (Refs. 3
to 5). Based on the results of cognitive
interviews, we have revised the
measurement of behavioral intention to
the following: ‘‘If you were considering
prescribing [DRUG] to a patient with
[DISEASE], how important would the
information in the [DISPLAY FILL] be
in your decision making?’’
Questions 14 to 23 provide important
information to address the research
questions for this study, including
sources of information for studies that
do not support an off-label use as well
as what aspects of the study would be
most important to prescribers.
Questions 10 and 11 are intended to
evaluate whether there is enough
information for the participants to make
a prescribing decision based on the
information in the brief study report and
disclosure condition, not to assess the
adequacy of pharmaceutical firms’
disclosure of unsupportive data
generally. Pharmaceutical firms are not
referenced in any study materials, and
these questions do not imply anything
about their dissemination activities.
(Comment 6) One comment
recommended that the stimuli used to
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represent publications that reach
contrary or different conclusions
regarding the unapproved use be held to
the same standards as the publication
about the unapproved use. The
comment suggests that this should
include being considered scientifically
sound by experts with scientific training
and expertise to evaluate the safety or
effectiveness of the drug or device.
(Response 6) Both the supportive and
unsupportive data provided to study
participants either in the form of
publications or summary information
were reviewed by FDA experts with the
requisite scientific training and
experience to ensure they are
appropriate, realistic, and of similar
quality.
(Comment 7) One comment
recommended that the disclosure
summary include specific information
about the study design (i.e., study
population and control group, key
clinical endpoints (patient outcomes)),
statistical significance (i.e., 95 percent
confidence interval (CI), hazard ratio
(HR) and p value) and other key data
needed to determine benefit-risk ratio,
and to include the product
manufacturer and study sponsor.
(Response 7) The proposed
experimental study design includes five
conditions to examine disclosure
approaches for communicating
unsupportive information. One of the
five conditions provides study details as
recommended by the comment. The
other conditions have varying levels of
detail about the unsupportive
information about the unapproved new
use of the prescription drug. There is
also a control condition. We have
purposely omitted the product
manufacturer and study sponsor, as we
know from other research this may
unduly influence physicians’ beliefs
about the quality of the study (Ref. 6).
(Comment 8) One comment suggested
the disclosure correlate with the
unapproved use described in the brief
study report.
(Response 8) We agree with this point.
The disclosure and unsupportive data
provided to participants are relevant to
the unapproved use information
participants initially review.
(Comment 9) One comment suggested
including hyperlinks to a citation for the
data and including a representative
publication with unsupportive data.
This comment also suggested keeping
track of how many study participants
utilize the hyperlink.
(Response 9) We developed the
stimuli for this study using information
from multiple scientific publications.
Thus, the content does not represent
one particular study, and we are unable
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to provide hyperlinks. The revised
design suggested in the comment may
be a good suggestion for future research.
Several comments suggested changes
to the proposed questionnaire.
(Comment 10) One comment
suggested the instructions and lack of a
‘‘don’t know’’ response option may lead
to forced guessing, which may
undermine the utility of the study.
(Response 10) We have deleted
Question 10 and revised Question 11 to
read, ‘‘What additional information, if
any, did you need in order to consider
prescribing [DRUG] for [DISEASE]?’’
and deleted the instructions to ‘‘give us
your best guess on answers you do not
know.’’
(Comment 11) One comment
recommends FDA focus on HCPs’
understanding of the data rather than
asking about HCPs’ preference for
receiving information (Q19 and Q20).
(Response 11) In response to the
comment, we have removed Questions
19 and 20 from the survey. Question 3
(now Q4) assesses physician
understanding of the disclosure.
(Comment 12) One comment
suggested deleting or revising Questions
6 and 9 because outside influences
could skew the results.
(Response 12) We are examining the
impact of the various levels of
information disclosure on participants’
ratings of how informative they find the
information and how likely they would
be to search for additional information
about the drug. Participants will be
randomly assigned to a condition, and
any individual differences or potential
biases should be spread across
experimental conditions. Thus, if we
find differences between and among
conditions, we can be reasonably certain
that the study manipulations caused the
differences. In consideration of this
comment and feedback from peer
reviewers, we have revised Question 6
(now Q7) to read, ‘‘If you were
considering prescribing [DRUG] for
[DISEASE], how useful would the
information [DISPLAY FILL] be?’’
(Comment 13) One comment
suggested deleting or revising Question
8 because it is unclear what it means for
information to be ‘‘credible’’ in this
context, and assessing credibility is very
subjective.
(Response 13) To clarify, this question
reads, ‘‘How credible is the information
presented [DISPLAY FILL]?’’ where
[DISPLAY FILL] in Condition 1 is ‘‘on
page 2,’’ in Conditions 2, 3, and 4 is the
text of the disclosure condition to which
they have been assigned, and in
Condition 5 is ‘‘the material.’’ Thus, the
information on which participants are
being asked to give their opinion is
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specified. This question has been used
in other studies without difficulty.
Cognitive testing did not identify any
difficulty with respondents’
understanding of ‘‘credible’’ in this
context.
(Comment 14) One comment
suggested amending questions that are
worded ‘‘contradict or do not support’’
because physicians may view a lack of
support (inconclusive findings) as
different from contradictory findings.
(Response 14) We did not intend for
‘‘do not support’’ to mean that the
findings are inconclusive, although we
acknowledge that it could be interpreted
in such a way. Our intention was to
refer to any findings that do not support
the off-label use, such as findings that
the drug is not effective for the off-label
use or had increased risks. We explored
potential confusion by asking separate
questions on the concepts of
‘‘contradict’’ and ‘‘inconclusive’’ in
cognitive testing. Cognitive testing
suggested that respondents generally
considered ‘‘findings that contradict’’
and ‘‘findings that have inconclusive
support’’ to be very similar concepts.
While respondents agreed that the two
were technically distinct, they tended to
assess the two similarly in this context.
To gather additional empirical data, we
will retain these as separate items in the
pretest.
(Comment 15) One comment suggests
many of the questions use unbalanced
answer scales and recommends the
answer scales should be balanced. For
example, it may be difficult for
participants to distinguish between ‘‘A
little’’ and ‘‘Somewhat’’ or ‘‘Very’’ and
‘‘Extremely.’’ Relatedly, the positive and
negative options are not necessarily
opposites (e.g., ‘‘Agree’’ or ‘‘Disagree’’)
or parallel in intensity (e.g., ‘‘Strongly
Agree’’ or ‘‘Strongly Disagree’’).
(Response 15) We are not using a
bipolar scale measuring opposites.
Bipolar scales are typically used when
there are two opposing possibilities
(e.g., ‘‘Strongly Agree’’ or ‘‘Strongly
Disagree’’). We chose a unipolar scale
(e.g., ‘‘not at all important’’ to
‘‘extremely important’’) because the
questions are asking about the relative
presence or absence of a quality. In the
case of usefulness, for instance, it makes
more sense for the scale to begin with
the absence of usefulness (‘‘not at all
useful’’) rather than the opposite of
usefulness (‘‘extremely useless’’). By
beginning with ‘‘Not at all,’’ the order of
the scale balances out the
unidimensional nature of the question
(Ref. 7). In fact, a key advantage of a
unipolar scale is that it does not depend
on defining opposites. The scale labels
(i.e., ‘‘Not at all,’’ ‘‘A little,’’
PO 00000
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Sfmt 4703
‘‘Somewhat,’’ ‘‘Very,’’ and ‘‘Extremely’’)
have been tested in multiple studies,
and evidence shows that participants
are able to distinguish between the
response options (see, for example, Ref.
8).
(Comment 16) One comment
expressed a lack of clarity on how
Question 3 could yield interpretable
responses and recommended replacing
this open-ended question with closedended questions.
(Response 16) Open-ended items are
often used when the intention is to
understand respondents’
comprehension (Ref. 9). By asking
respondents to rephrase the disclosure
in their own words (as if explaining to
a colleague), we can assess whether
respondents understand the disclosure
language as intended (Ref. 10). The
responses to open-ended items are
qualitative data and will be analyzed to
assess what respondents feel to be key
information (information included in
their summary), what they feel is
extraneous information (information not
included in their summary), and any
information that is confusing or unclear
(information summarized incorrectly in
the summary).
(Comment 17) One comment
suggested adding the following
questions to the questionnaire:
1. How often do you research and
study off-label uses of approved drugs
in a given week? With possible answer
choices being ‘‘never, rarely,
occasionally, frequently.’’
2. How often are drug products used
off-label in your practice? With possible
answer choices being ‘‘never, rarely,
occasionally, frequently.’’
3. Would you prescribe this drug for
(unapproved use of an approved drug
product)? With possible answer choices
being: ‘‘yes, no, need more
information.’’
(Response 17) For the first suggested
question, we currently assess frequency
of prescribing a drug off label (Q14) and
the sources used to learn about off-label
uses (old Q15 and old Q16, now Q17,
Q18, and Q19). We think this
combination of questions adequately
covers the concept of how often
participants prescribe and look for
information about off-label uses.
Regarding the response choices, the
timeframe of a week is very narrow, and
would be difficult to answer for those
who prescribe off-label infrequently
(e.g., a few times a year). In response to
the comment and external peer review
comment, we have revised response
options for Q14 to be more specific
(once a week or more often, several
times each month, several times each
E:\FR\FM\11JNN1.SGM
11JNN1
31323
Federal Register / Vol. 86, No. 111 / Friday, June 11, 2021 / Notices
year, less than once a year, have never
prescribed a drug for an off-label use).
For the second suggestion, we agree
that the frequency of prescribing within
the practice would be useful to capture
and have added a question to measure
this. No difficulties were identified with
this question during cognitive testing.
For the third suggestion, we agree that
this would be a useful measure. In
response to this comment and peer
review, we have revised the
questionnaire to ask about prescribing
likelihood for the specific off-label use.
FDA estimates the burden of this
collection of information as follows:
TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1
Number of
respondents
Activity
Average
burden per
response
Total annual
responses
Pretest screener ...........................................................
Pretest completes .........................................................
Main study screener .....................................................
Main study completes, Medical Condition 1 ................
Main study completes, Medical Condition 2 ................
290
180
2,526
510
1,090
1
1
1
1
1
290
180
2,526
510
1,090
Total ......................................................................
1,600
........................
........................
1 There
0.08
0.33
0.08
0.33
0.33
Total hours
(5 minutes) ....
(20 minutes) ..
(5 minutes) ....
(20 minutes) ..
(20 minutes) ..
23
59
202
168
360
...............................
812
are no capital costs or operating and maintenance costs associated with this collection of information.
II. References
The following references marked with
an asterisk (*) are on display at the
Dockets Management Staff (HFA–305),
Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD
20852, 240–402–7500 and are available
for viewing by interested persons
between 9 a.m. and 4 p.m., Monday
through Friday; they also are available
electronically at https://
www.regulations.gov. References
without asterisks are not on public
display at https://www.regulations.gov
because they have copyright restriction.
Some may be available at the website
address, if listed. References without
asterisks are available for viewing only
at the Dockets Management Staff. FDA
has verified the website addresses, as of
the date this document publishes in the
Federal Register, but websites are
subject to change over time.
jbell on DSKJLSW7X2PROD with NOTICES
Number of
responses
per
respondent
*1. ‘‘Distributing Scientific and Medical
Publications on Unapproved New Uses—
Recommended Practices—Revised Draft
Guidance,’’ 2014. https://www.fda.gov/
downloads/Drugs/GuidanceCompliance
RegulatoryInformation/Guidances/
UCM387652.pdf.
*2. ‘‘Responding to Unsolicited Requests for
Off-Label Information About Prescription
Drugs and Medical Devices Draft
Guidance,’’ 2011. https://www.fda.gov/
media/82660/download.
3. Ajzen, I. 1985. ‘‘From Intentions to
Actions: A Theory of Planned Behavior.’’
In: Action Control: From Cognition to
Behavior, edited by J. Kuhl and J.
Beckmann, pp. 11–39. Berlin, Heidelber,
New York: Springer-Verlag.
4. Murshid, M.A. and Z. Mohaidin. 2017.
‘‘Models and Theories of Prescribing
Decisions: A Review and Suggested a
New Model.’’ Pharmacy Practice, 15(2),
990.
*5. Sable M.R., L.R. Schwartz, P.J. Kelly, et
al. 2006. ‘‘Using the Theory of Reasoned
VerDate Sep<11>2014
19:14 Jun 10, 2021
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Action to Explain Physician Intention to
Prescribe Emergency Contraception.’’
Perspectives on Sexual and Reproductive
Health, 38(1), pp. 20–27. https://
www.guttmacher.org/journals/psrh/
2006/using-theory-reasoned-actionexplain-physician-intention-prescribe.
6. Kesselheim, A.S., C.T. Robertson, J.A.
Myers, et al. 2012. ‘‘A Randomized
Study of How Physicians Interpret
Research Funding Disclosures.’’ New
England Journal of Medicine, 367(12),
pp. 1119–1127.
7. Schaeffer, N.C. and S. Presser. 2003. ‘‘The
Science of Asking Questions.’’ Annual
Review of Sociology, 29.
8. Fox, J., M. Earp, and R. Kaplan. 2020.
‘‘Item Scale Performance.’’ 75th Annual
American Association for Public
Opinion Research Virtual Conference.
9. Ozuru, Y., S. Briner, C.A. Kurby, et al.
2013. ‘‘Comparing Comprehension
Measured by Multiple-Choice and OpenEnded Questions. Canadian Journal of
Experimental Psychology = Revue
canadienne de psychologie
experimentale, 67(3), pp. 215–227.
10. Tanur, J.M. (Ed.). 1992. Questions About
Questions: Inquiries Into the Cognitive
Bases of Surveys. Russell Sage
Foundation.
Dated: June 2, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for
Policy.
[FR Doc. 2021–12265 Filed 6–10–21; 8:45 am]
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2021–N–0371]
Agency Information Collection
Activities; Proposed Collection;
Comment Request; Accelerated
Approval Disclosures on Direct-toConsumer Prescription Drug Websites
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA, Agency, or we) is
announcing an opportunity for public
comment on the proposed collection of
certain information by the Agency.
Under the Paperwork Reduction Act of
1995 (PRA), Federal Agencies are
required to publish notice in the
Federal Register concerning each
proposed collection of information and
to allow 60 days for public comment in
response to the notice. This notice
solicits comments on the proposed
study entitled ‘‘Accelerated Approval
Disclosures on Direct-to-Consumer
Prescription Drug websites.’’
DATES: Submit either electronic or
written comments on the collection of
information by August 10, 2021.
ADDRESSES: You may submit comments
as follows. Please note that late,
untimely filed comments will not be
considered. Electronic comments must
be submitted on or before August 10,
2021. The https://www.regulations.gov
electronic filing system will accept
comments until 11:59 p.m. Eastern Time
at the end of August 10, 2021.
Comments received by mail/hand
delivery/courier (for written/paper
SUMMARY:
E:\FR\FM\11JNN1.SGM
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]]>Agencies
[Federal Register Volume 86, Number 111 (Friday, June 11, 2021)]
[Notices]
[Pages 31318-31323]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-12265]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2020-N-1261]
Agency Information Collection Activities; Submission for Office
of Management and Budget Review; Comment Request; Study of Disclosures
to Healthcare Providers Regarding Data That Do Not Support Unapproved
Use of an Approved Prescription Drug
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is
announcing that a proposed collection of information has been submitted
to the Office of Management and Budget (OMB) for review and clearance
under the Paperwork Reduction Act of 1995 (PRA).
DATES: Submit written comments (including recommendations) on the
collection of information by July 12, 2021.
[[Page 31319]]
ADDRESSES: To ensure that comments on the information collection are
received, OMB recommends that written comments be submitted to https://www.reginfo.gov/public/do/PRAMain. Find this particular information
collection by selecting ``Currently under Review--Open for Public
Comments'' or by using the search function. The title of this
information collection is ``Study of Disclosures to Healthcare
Providers Regarding Data That Do Not Support Unapproved Use of an
Approved Prescription Drug.'' Also include the FDA docket number found
in brackets in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Ila S. Mizrachi, Office of Operations,
Food and Drug Administration, Three White Flint North, 10A-12M, 11601
Landsdown St., North Bethesda, MD 20852, 301-796-7726,
[email protected].
SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has
submitted the following proposed collection of information to OMB for
review and clearance.
Study of Disclosures to Healthcare Providers Regarding Data That Do Not
Support Unapproved Use of an Approved Prescription Drug
OMB Control Number 0910-New
I. Background
Section 1701(a)(4) of the Public Health Service Act (42 U.S.C.
300u(a)(4)) authorizes FDA to conduct research relating to health
information. Section 1003(d)(2)(C) of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) (21 U.S.C. 393(d)(2)(C)) authorizes FDA to
conduct research relating to drugs and other FDA-regulated products in
carrying out the provisions of the FD&C Act.
The Office of Prescription Drug Promotion's (OPDP's) mission is to
protect the public health by helping to ensure that prescription drug
promotion is truthful, balanced, and accurately communicated. OPDP's
research program provides scientific evidence to help ensure that our
policies related to prescription drug promotion will have the greatest
benefit to public health. Toward that end, we have consistently
conducted research to evaluate the aspects of prescription drug
promotion that are most central to our mission. Our research focuses in
particular on three main topic areas: Advertising features, including
content and format; target populations; and research quality. Through
the evaluation of advertising features, we assess how elements such as
graphics, format, and disease and product characteristics impact the
communication and understanding of prescription drug risks and
benefits; focusing on target populations allows us to evaluate how
understanding of prescription drug risks and benefits may vary as a
function of audience; and our focus on research quality aims at
maximizing the quality of our research data through analytical
methodology development and investigation of sampling and response
issues. This study will inform the first two topic areas: Advertising
features and target populations.
Because we recognize that the strength of data and the confidence
in the robust nature of the findings is improved by utilizing the
results of multiple converging studies, we continue to develop evidence
to inform our thinking. We evaluate the results from our studies within
the broader context of research and findings from other sources, and
this larger body of knowledge collectively informs our policies as well
as our research program. Our research is documented on our homepage,
which can be found at: https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm090276.htm. The website
includes links to the latest Federal Register notices and peer-reviewed
publications produced by our office. The website maintains information
on studies we have conducted, dating back to a survey on direct-to-
consumer advertisements conducted in 1999.
The revised draft guidance entitled ``Distributing Scientific and
Medical Publications on Unapproved New Uses--Recommended Practices''
(2014; Ref. 1),\1\ recommends that scientific and medical journal
articles that discuss unapproved uses of approved drug products be
disseminated with a representative publication that reaches contrary or
different conclusions, when such information exists. Similarly, the
draft guidance entitled ``Responding to Unsolicited Requests for Off-
Label Information About Prescription Drugs and Medical Devices'' (2011;
Ref. 2) \1\ recommends that when conclusions of articles or texts that
are disseminated in response to an unsolicited request have been
specifically called into question by other articles or texts, a firm
should disseminate representative publications that reach contrary or
different conclusions regarding the use at issue.
---------------------------------------------------------------------------
\1\ When final, this guidance will represent the FDA's current
thinking on this topic.
---------------------------------------------------------------------------
Pharmaceutical firms sometimes choose to disseminate publications
to healthcare providers (HCPs) that include data that appear to support
an unapproved use of an approved product. At the same time, published
data that are not supportive of that unapproved use may also exist. For
example, unsupportive published information could describe an increased
risk of negative outcomes (e.g., death, relapse) from the unapproved
use of the approved product, suggesting that the unapproved use does
not have a positive benefit-risk ratio. The purpose of this research is
to examine physicians' perceptions and behavioral intentions about an
unapproved new use of an approved prescription drug when made aware of
other data that are not supportive of the unapproved use. This research
will also evaluate the effectiveness of various disclosure approaches
for communicating the unsupportive information. We will use the results
of this research to better understand: (1) Physicians' perceptions of
an unapproved use of a prescription drug; (2) physicians' perceptions
about an unapproved use of an approved prescription drug when they are
aware of the existence of unsupportive information about it; (3)
physicians' perceptions of disclosures referencing the existence of
unsupportive information about that particular use; and (4) to examine
the utility and effectiveness of various approaches to the
communication of this information. In particular, we plan to examine
how different approaches to the communication of unsupportive
information affect physicians' thoughts and attitudes about the
unapproved use. Five approaches will be examined: (1) The provision of
the unsupportive data in the form of a representative publication; (2)
a disclosure that summarizes, rather than provides, the unsupportive
data and includes a citation to the representative publication; (3) a
disclosure that does not provide or include a summary of the
unsupportive data but does acknowledge that unsupportive data exist and
includes a citation to the representative publication; (4) a general
disclosure that does not provide or include a summary of the
unsupportive data but acknowledges unsupportive data may exist, without
conceding that such data do exist; or (5) nothing--the absence of any
presentation of unsupportive data or any disclosure about such data
(control condition). We have four research questions:
RQ1: When considering a presentation of data about an unapproved
use of an approved drug product, how does the existence of unsupportive
data impact physicians'
[[Page 31320]]
perceptions and intentions with regard to that unapproved use?
RQ2: How does the way in which the existence of unsupportive data
is communicated, when the specific data is not presented, impact
physicians' perceptions and intentions with regard to an unapproved use
of an approved drug product?
RQ3: How are physicians' perceptions of and intentions toward an
unapproved use of an approved drug product affected by the disclosure
of specific unsupportive data versus disclosure statements about data
that is not presented?
RQ4: Do other variables (e.g., demographics) have an impact on
these effects? These research questions will be examined in two medical
conditions.
We plan to conduct one pretest with 180 voluntary adult
participants and one main study with 1,600 voluntary adult
participants. Participants in the main study will be 510 oncologists in
the oncology medical condition and 1,090 primary care physicians in the
insomnia \2\ medical condition. All participants will be physicians who
engage in patient care at least 50 percent of the time and do not work
for a pharmaceutical company, marketing firm, or the Department of
Health and Human Services. The gender, race/ethnicity, and ages of the
participating physicians will be self-identified by participants. We
will aim to include a mix of demographic segments to ensure a diversity
of viewpoints and backgrounds. Power analyses were conducted to ensure
adequate sample sizes to detect small to medium effects.
---------------------------------------------------------------------------
\2\ This medical condition was changed from diabetes to insomnia
based on cognitive testing.
---------------------------------------------------------------------------
The studies will be conducted online. The pretest and main studies
will have the same design and will follow the same procedure. The base
stimulus in both the pretest and main studies will consist of a sample
publication supporting an unapproved use of an approved drug product.
Within each medical condition, participants will be randomly assigned
to one of five test conditions (see figure 1). Following exposure to
the stimuli, they will be asked to complete a questionnaire that
assesses comprehension, perceptions, prescribing intentions, and
demographics. In the pretest, participants will also answer questions
about the study design and questionnaire.
Figure 1--Study Design
--------------------------------------------------------------------------------------------------------------------------------------------------------
Accompanied by
Accompanied by disclosure that
Accompanied by disclosure with unsupportive data Accompanied by
representative summary of exist and including a general disclosure No disclosure or
publication with unsupportive data and citation for that that unsupportive material about
unsupportive data including a citation data, but without a data may exist and no unsupportive data
for that data summary of the citation
unsupportive data
--------------------------------------------------------------------------------------------------------------------------------------------------------
Medical Condition 1
Medical Condition 2
--------------------------------------------------------------------------------------------------------------------------------------------------------
In the Federal Register of July 6, 2020 (85 FR 40300), FDA
published a 60-day notice requesting public comment on the proposed
collection of information. FDA received two submissions that were PRA-
related. Within these submissions FDA received multiple comments that
the Agency has addressed below. For brevity, some public comments are
paraphrased and, therefore, may not include the exact language used by
the commenter. We assure commenters that the entirety of their comments
was considered even if not fully captured by our paraphrasing in this
document. The following acronyms are used here: HCP = healthcare
provider; FDA and ``The Agency'' = Food and Drug Administration; OPDP =
FDA's Office of Prescription Drug Promotion.
(Comment 1) One comment asserted that FDA has not made the stimuli
available for public comment and requested FDA publish a new 60-day
notice after these comments have been addressed to give the public
another opportunity to review and comment.
(Response 1) We have provided the purpose of the study, the design,
the population of interest, and the questionnaire to individuals upon
request. These materials have proven sufficient for public comment and
for academic experts to peer review the study successfully. Our full
stimuli are under development during the PRA process. We do not make
draft stimuli public during this time because of concerns that this may
contaminate our participant pool and compromise the research.
(Comment 2) One comment suggested that due to the task of reading
the ``scientific publication'' stimuli and length of the questionnaire,
FDA's estimation of the time it will take to complete the study is too
low, and thus the burden of the information collection is inaccurate.
(Response 2) The scientific ``publications'' in this study are each
formatted as a one-page brief report. The text is presented in two
columns and has the following headings: Introduction, Methods, Results,
Discussion, and Limitations. The survey contains primarily closed-ended
questions with Likert scales, and there are five open-ended questions.
The expected time for the study is based on our prior experience
conducting studies using similar protocols. We will also test the time
during the pretest to ensure we stay within 20 minutes. If we determine
the average time for completing the survey is greater than 20 minutes,
we will revise the survey prior to fielding the main study.
(Comment 3) One comment asserts this proposed study overlaps with
other OPDP research currently in progress and references several
studies.
(Response 3) OPDP may conduct concurrent or overlapping studies on
similar topics. While the studies referenced by the comment contribute
to the evidence base for prescription drug promotion, prior studies had
a different focus than the current study. Prior disclosure studies
examined the effectiveness of disclosures in increasing understanding
of efficacy claims (``Disclosures in Professional and Consumer
Prescription Drug Promotion'') and the role of disclosures in
mitigating potentially misleading presentations of preliminary or
descriptive data about oncology drugs (``Disclosures of Descriptive
[[Page 31321]]
Presentations in Professional Oncology Prescription Drug Promotion'').
The third study mentioned by the comment (``Physician Interpretation of
Information About Prescription Drugs in Scientific Publications vs.
Promotional Pieces'') investigates how physician perception of
professional prescription drug communications is influenced by
variations in information context, methodologic rigor of the clinical
study, and time pressure.
The current study uses an experimental design to compare various
disclosure approaches for communicating unsupportive information about
an unapproved new use. The findings of this study will help inform
FDA's understanding about when disclosures about unsupportive data
might be useful and what types of information should be included.
(Comment 4) One comment expressed concern that the way in which the
proposed research is described in the notice suggests that
pharmaceutical firms disseminate supportive data but do not adequately
disclose unsupportive data and that this ``implied bias'' may taint the
collection and interpretation of the data.
(Response 4) The sentences referred to in this comment appear in
the Federal Register notices for the study to provide background and do
not suggest that any firms are not following the recommendations in the
two guidance documents referenced in that same background section.
Rather, the background outlines the current FDA recommendations around
disclosure of unsupportive data with these types of communications and
the intent of the study to evaluate alternative approaches to the
disclosure of unsupportive data. These background statements are not
part of the materials that will be provided to study participants.
Rather, study instructions tell participants only that they will be
reviewing informational material about a prescription drug. No
instructional materials provided to participants mention a
pharmaceutical manufacturer. Therefore, we do not believe the
collection and interpretation of study findings will be tainted or
biased.
(Comment 5) One comment suggested deleting or amending all
questions about HCPs' prescribing decisions (Questions 4, 5, 10, 11, 14
to 23) because these decisions are likely to be influenced by many
factors and are outside of FDA's jurisdiction. This comment also
asserted Question 10 is biased and worded to suggest that
pharmaceutical firms disseminate supportive data but do not adequately
disclose unsupportive data and suggests deleting or amending the
question.
(Response 5) As explained earlier, the Public Health Service Act
authorizes FDA to conduct research relating to health information, and
the FD&C Act authorizes FDA to conduct research relating to drugs and
other FDA-regulated products in carrying out the provisions of the FD&C
Act. The purpose of the current experimental study is to examine
physicians' perceptions and behavioral intentions about an unapproved
new use of an approved prescription drug when made aware of other data
that are not supportive of the unapproved use and to evaluate the
effectiveness of various disclosure approaches for communicating the
unsupportive information. The study is within FDA's authority, and it
will help to inform OPDP's work to help ensure that prescription drug
information is truthful, balanced, and accurately communicated so that
HCPs and consumers can make informed decisions.
Questions 4 and 5 were intended to assess the impact of various
disclosure manipulations on hypothetical prescribing decisions.
Measuring behavioral intention is a common method of assessing
knowledge and attitudes. There is substantial theoretical and empirical
support for our approach, and strong behavioral intention has been
shown to be predictive across a wide range of behaviors, including
prescribing (Refs. 3 to 5). Based on the results of cognitive
interviews, we have revised the measurement of behavioral intention to
the following: ``If you were considering prescribing [DRUG] to a
patient with [DISEASE], how important would the information in the
[DISPLAY FILL] be in your decision making?''
Questions 14 to 23 provide important information to address the
research questions for this study, including sources of information for
studies that do not support an off-label use as well as what aspects of
the study would be most important to prescribers.
Questions 10 and 11 are intended to evaluate whether there is
enough information for the participants to make a prescribing decision
based on the information in the brief study report and disclosure
condition, not to assess the adequacy of pharmaceutical firms'
disclosure of unsupportive data generally. Pharmaceutical firms are not
referenced in any study materials, and these questions do not imply
anything about their dissemination activities.
(Comment 6) One comment recommended that the stimuli used to
represent publications that reach contrary or different conclusions
regarding the unapproved use be held to the same standards as the
publication about the unapproved use. The comment suggests that this
should include being considered scientifically sound by experts with
scientific training and expertise to evaluate the safety or
effectiveness of the drug or device.
(Response 6) Both the supportive and unsupportive data provided to
study participants either in the form of publications or summary
information were reviewed by FDA experts with the requisite scientific
training and experience to ensure they are appropriate, realistic, and
of similar quality.
(Comment 7) One comment recommended that the disclosure summary
include specific information about the study design (i.e., study
population and control group, key clinical endpoints (patient
outcomes)), statistical significance (i.e., 95 percent confidence
interval (CI), hazard ratio (HR) and p value) and other key data needed
to determine benefit-risk ratio, and to include the product
manufacturer and study sponsor.
(Response 7) The proposed experimental study design includes five
conditions to examine disclosure approaches for communicating
unsupportive information. One of the five conditions provides study
details as recommended by the comment. The other conditions have
varying levels of detail about the unsupportive information about the
unapproved new use of the prescription drug. There is also a control
condition. We have purposely omitted the product manufacturer and study
sponsor, as we know from other research this may unduly influence
physicians' beliefs about the quality of the study (Ref. 6).
(Comment 8) One comment suggested the disclosure correlate with the
unapproved use described in the brief study report.
(Response 8) We agree with this point. The disclosure and
unsupportive data provided to participants are relevant to the
unapproved use information participants initially review.
(Comment 9) One comment suggested including hyperlinks to a
citation for the data and including a representative publication with
unsupportive data. This comment also suggested keeping track of how
many study participants utilize the hyperlink.
(Response 9) We developed the stimuli for this study using
information from multiple scientific publications. Thus, the content
does not represent one particular study, and we are unable
[[Page 31322]]
to provide hyperlinks. The revised design suggested in the comment may
be a good suggestion for future research.
Several comments suggested changes to the proposed questionnaire.
(Comment 10) One comment suggested the instructions and lack of a
``don't know'' response option may lead to forced guessing, which may
undermine the utility of the study.
(Response 10) We have deleted Question 10 and revised Question 11
to read, ``What additional information, if any, did you need in order
to consider prescribing [DRUG] for [DISEASE]?'' and deleted the
instructions to ``give us your best guess on answers you do not know.''
(Comment 11) One comment recommends FDA focus on HCPs'
understanding of the data rather than asking about HCPs' preference for
receiving information (Q19 and Q20).
(Response 11) In response to the comment, we have removed Questions
19 and 20 from the survey. Question 3 (now Q4) assesses physician
understanding of the disclosure.
(Comment 12) One comment suggested deleting or revising Questions 6
and 9 because outside influences could skew the results.
(Response 12) We are examining the impact of the various levels of
information disclosure on participants' ratings of how informative they
find the information and how likely they would be to search for
additional information about the drug. Participants will be randomly
assigned to a condition, and any individual differences or potential
biases should be spread across experimental conditions. Thus, if we
find differences between and among conditions, we can be reasonably
certain that the study manipulations caused the differences. In
consideration of this comment and feedback from peer reviewers, we have
revised Question 6 (now Q7) to read, ``If you were considering
prescribing [DRUG] for [DISEASE], how useful would the information
[DISPLAY FILL] be?''
(Comment 13) One comment suggested deleting or revising Question 8
because it is unclear what it means for information to be ``credible''
in this context, and assessing credibility is very subjective.
(Response 13) To clarify, this question reads, ``How credible is
the information presented [DISPLAY FILL]?'' where [DISPLAY FILL] in
Condition 1 is ``on page 2,'' in Conditions 2, 3, and 4 is the text of
the disclosure condition to which they have been assigned, and in
Condition 5 is ``the material.'' Thus, the information on which
participants are being asked to give their opinion is specified. This
question has been used in other studies without difficulty. Cognitive
testing did not identify any difficulty with respondents' understanding
of ``credible'' in this context.
(Comment 14) One comment suggested amending questions that are
worded ``contradict or do not support'' because physicians may view a
lack of support (inconclusive findings) as different from contradictory
findings.
(Response 14) We did not intend for ``do not support'' to mean that
the findings are inconclusive, although we acknowledge that it could be
interpreted in such a way. Our intention was to refer to any findings
that do not support the off-label use, such as findings that the drug
is not effective for the off-label use or had increased risks. We
explored potential confusion by asking separate questions on the
concepts of ``contradict'' and ``inconclusive'' in cognitive testing.
Cognitive testing suggested that respondents generally considered
``findings that contradict'' and ``findings that have inconclusive
support'' to be very similar concepts. While respondents agreed that
the two were technically distinct, they tended to assess the two
similarly in this context. To gather additional empirical data, we will
retain these as separate items in the pretest.
(Comment 15) One comment suggests many of the questions use
unbalanced answer scales and recommends the answer scales should be
balanced. For example, it may be difficult for participants to
distinguish between ``A little'' and ``Somewhat'' or ``Very'' and
``Extremely.'' Relatedly, the positive and negative options are not
necessarily opposites (e.g., ``Agree'' or ``Disagree'') or parallel in
intensity (e.g., ``Strongly Agree'' or ``Strongly Disagree'').
(Response 15) We are not using a bipolar scale measuring opposites.
Bipolar scales are typically used when there are two opposing
possibilities (e.g., ``Strongly Agree'' or ``Strongly Disagree''). We
chose a unipolar scale (e.g., ``not at all important'' to ``extremely
important'') because the questions are asking about the relative
presence or absence of a quality. In the case of usefulness, for
instance, it makes more sense for the scale to begin with the absence
of usefulness (``not at all useful'') rather than the opposite of
usefulness (``extremely useless''). By beginning with ``Not at all,''
the order of the scale balances out the unidimensional nature of the
question (Ref. 7). In fact, a key advantage of a unipolar scale is that
it does not depend on defining opposites. The scale labels (i.e., ``Not
at all,'' ``A little,'' ``Somewhat,'' ``Very,'' and ``Extremely'') have
been tested in multiple studies, and evidence shows that participants
are able to distinguish between the response options (see, for example,
Ref. 8).
(Comment 16) One comment expressed a lack of clarity on how
Question 3 could yield interpretable responses and recommended
replacing this open-ended question with closed-ended questions.
(Response 16) Open-ended items are often used when the intention is
to understand respondents' comprehension (Ref. 9). By asking
respondents to rephrase the disclosure in their own words (as if
explaining to a colleague), we can assess whether respondents
understand the disclosure language as intended (Ref. 10). The responses
to open-ended items are qualitative data and will be analyzed to assess
what respondents feel to be key information (information included in
their summary), what they feel is extraneous information (information
not included in their summary), and any information that is confusing
or unclear (information summarized incorrectly in the summary).
(Comment 17) One comment suggested adding the following questions
to the questionnaire:
1. How often do you research and study off-label uses of approved
drugs in a given week? With possible answer choices being ``never,
rarely, occasionally, frequently.''
2. How often are drug products used off-label in your practice?
With possible answer choices being ``never, rarely, occasionally,
frequently.''
3. Would you prescribe this drug for (unapproved use of an approved
drug product)? With possible answer choices being: ``yes, no, need more
information.''
(Response 17) For the first suggested question, we currently assess
frequency of prescribing a drug off label (Q14) and the sources used to
learn about off-label uses (old Q15 and old Q16, now Q17, Q18, and
Q19). We think this combination of questions adequately covers the
concept of how often participants prescribe and look for information
about off-label uses. Regarding the response choices, the timeframe of
a week is very narrow, and would be difficult to answer for those who
prescribe off-label infrequently (e.g., a few times a year). In
response to the comment and external peer review comment, we have
revised response options for Q14 to be more specific (once a week or
more often, several times each month, several times each
[[Page 31323]]
year, less than once a year, have never prescribed a drug for an off-
label use).
For the second suggestion, we agree that the frequency of
prescribing within the practice would be useful to capture and have
added a question to measure this. No difficulties were identified with
this question during cognitive testing.
For the third suggestion, we agree that this would be a useful
measure. In response to this comment and peer review, we have revised
the questionnaire to ask about prescribing likelihood for the specific
off-label use.
FDA estimates the burden of this collection of information as
follows:
Table 1--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Activity Number of responses per Total annual Average burden per response Total hours
respondents respondent responses
--------------------------------------------------------------------------------------------------------------------------------------------------------
Pretest screener.............................. 290 1 290 0.08 (5 minutes)........................ 23
Pretest completes............................. 180 1 180 0.33 (20 minutes)....................... 59
Main study screener........................... 2,526 1 2,526 0.08 (5 minutes)........................ 202
Main study completes, Medical Condition 1..... 510 1 510 0.33 (20 minutes)....................... 168
Main study completes, Medical Condition 2..... 1,090 1 1,090 0.33 (20 minutes)....................... 360
---------------------------------------------------------------------------------------------------------
Total..................................... 1,600 .............. .............. ........................................ 812
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
II. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-
402-7500 and are available for viewing by interested persons between 9
a.m. and 4 p.m., Monday through Friday; they also are available
electronically at https://www.regulations.gov. References without
asterisks are not on public display at https://www.regulations.gov
because they have copyright restriction. Some may be available at the
website address, if listed. References without asterisks are available
for viewing only at the Dockets Management Staff. FDA has verified the
website addresses, as of the date this document publishes in the
Federal Register, but websites are subject to change over time.
*1. ``Distributing Scientific and Medical Publications on Unapproved
New Uses--Recommended Practices--Revised Draft Guidance,'' 2014.
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM387652.pdf.
*2. ``Responding to Unsolicited Requests for Off-Label Information
About Prescription Drugs and Medical Devices Draft Guidance,'' 2011.
https://www.fda.gov/media/82660/download.
3. Ajzen, I. 1985. ``From Intentions to Actions: A Theory of Planned
Behavior.'' In: Action Control: From Cognition to Behavior, edited
by J. Kuhl and J. Beckmann, pp. 11-39. Berlin, Heidelber, New York:
Springer-Verlag.
4. Murshid, M.A. and Z. Mohaidin. 2017. ``Models and Theories of
Prescribing Decisions: A Review and Suggested a New Model.''
Pharmacy Practice, 15(2), 990.
*5. Sable M.R., L.R. Schwartz, P.J. Kelly, et al. 2006. ``Using the
Theory of Reasoned Action to Explain Physician Intention to
Prescribe Emergency Contraception.'' Perspectives on Sexual and
Reproductive Health, 38(1), pp. 20-27. https://www.guttmacher.org/journals/psrh/2006/using-theory-reasoned-action-explain-physician-intention-prescribe.
6. Kesselheim, A.S., C.T. Robertson, J.A. Myers, et al. 2012. ``A
Randomized Study of How Physicians Interpret Research Funding
Disclosures.'' New England Journal of Medicine, 367(12), pp. 1119-
1127.
7. Schaeffer, N.C. and S. Presser. 2003. ``The Science of Asking
Questions.'' Annual Review of Sociology, 29.
8. Fox, J., M. Earp, and R. Kaplan. 2020. ``Item Scale
Performance.'' 75th Annual American Association for Public Opinion
Research Virtual Conference.
9. Ozuru, Y., S. Briner, C.A. Kurby, et al. 2013. ``Comparing
Comprehension Measured by Multiple-Choice and Open-Ended Questions.
Canadian Journal of Experimental Psychology = Revue canadienne de
psychologie experimentale, 67(3), pp. 215-227.
10. Tanur, J.M. (Ed.). 1992. Questions About Questions: Inquiries
Into the Cognitive Bases of Surveys. Russell Sage Foundation.
Dated: June 2, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-12265 Filed 6-10-21; 8:45 am]
BILLING CODE 4164-01-P
