[Federal Register Volume 86, Number 111 (Friday, June 11, 2021)]
[Notices]
[Pages 31323-31327]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-12264]


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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-to-Consumer 
Prescription Drug Websites

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: 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

[[Page 31324]]

submissions) will be considered timely if they are postmarked or the 
delivery service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2021-N-0371 for ``Agency Information Collection Activities; 
Proposed Collection; Comment Request; Accelerated Approval Disclosures 
on Direct-to-Consumer Prescription Drug websites.'' Received comments, 
those filed in a timely manner (see ADDRESSES), will be placed in the 
docket and, except for those submitted as ``Confidential Submissions,'' 
publicly viewable at https://www.regulations.gov or at the Dockets 
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

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]. The questionnaire is available upon request from 
[email protected].

SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3521), Federal 
Agencies must obtain approval from the Office of Management and Budget 
(OMB) for each collection of information they conduct or sponsor. 
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR 
1320.3(c) and includes Agency requests or requirements that members of 
the public submit reports, keep records, or provide information to a 
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) 
requires Federal Agencies to provide a 60-day notice in the Federal 
Register concerning each proposed collection of information before 
submitting the collection to OMB for approval. To comply with this 
requirement, FDA is publishing notice of the proposed collection of 
information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on these topics: (1) Whether the proposed collection 
of information is necessary for the proper performance of FDA's 
functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.

Accelerated Approval Disclosures on Direct-to-Consumer Prescription 
Drug Websites

OMB Control Number 0910-NEW

    Section 1701(a)(4) of the Public Health Service Act (42 U.S.C. 
300u(a)(4)) authorizes the 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) 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, focusing 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

[[Page 31325]]

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 topic area, advertising 
features, including content and format; and the second topic area, 
target populations.
    Because we recognize the strength of data and the confidence in the 
robust nature of the findings is improved through 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/about-fda/center-drug-evaluation-and-research-cder/office-prescription-drug-promotion-opdp-research. 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 direct-to-
consumer (DTC) survey conducted in 1999.

Background

    Pursuant to section 506(c) of the FD&C Act (21 U.S.C. 356(c)) and 
21 CFR part 314, subpart H (or 21 CFR part 601, subpart E for 
biological products), FDA may grant accelerated approval to a drug 
product under section 505(c) of the FD&C Act or a biological product 
under section 351(a) of the Public Health Service Act (42 U.S.C. 
262(a)). This pathway enables faster approval of prescription drugs 
intended to treat serious or life-threatening illnesses. Accelerated 
approval may be based on a determination that a drug product has an 
effect on a surrogate endpoint (for example, a blood test result) that 
is reasonably likely to predict clinical benefit, or on a clinical 
endpoint that can be measured earlier than irreversible morbidity or 
mortality, that is reasonably likely to predict an effect on 
irreversible morbidity or mortality or other clinical benefit (i.e., an 
intermediate clinical endpoint). In approving a drug under the 
accelerated approval pathway, the severity, rarity, or prevalence of a 
condition, and the availability or lack of alternative treatments, are 
taken into account.
    The accelerated approval pathway is limited to certain products 
intended to treat serious or life-threatening illnesses as there can be 
``[u]ncertainty about whether clinical benefit will be verified and the 
possibility of undiscovered risks'' (FDA 2014 guidance for industry 
entitled ``Expedited Programs for Serious Conditions--Drugs and 
Biologics,'' available at https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdf). Sponsors are generally required to conduct 
post approval studies to verify and describe the predicted clinical 
benefit, but those confirmatory studies are not complete at the time 
that the accelerated approval is granted (Ref. 1). In the event that 
the required post-approval confirmatory studies fail to verify and 
describe the predicted effect or clinical benefit, a drug's approval 
can be withdrawn using expedited procedures.
    Under FDA regulations governing physician labeling for prescription 
drugs, the INDICATIONS AND USAGE section of FDA-approved prescribing 
information for a drug approved under accelerated approval must include 
not only the indication (21 CFR 201.57(c)) but also a ``succinct 
description of the limitations of usefulness of the drug and any 
uncertainty about anticipated clinical benefits . . .'' (21 CFR 
201.57(c)(2)(i)(B)). In a guidance, FDA recommended that in addition to 
these required elements, the INDICATIONS AND USAGE section for drugs 
approved under accelerated approval should generally acknowledge that 
continued approval for the drug or indication may be contingent on 
verification and description of clinical benefit in confirmatory trials 
(FDA 2019 guidance for industry entitled ``Labeling for Human 
Prescription Drug and Biological Products Approved Under the 
Accelerated Approval Pathway,'' available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM390058.pdf).
    Some DTC websites have included disclosures about accelerated 
approval, and of those, many included similar content to that seen in 
the INDICATIONS AND USAGE section of approved labeling. A content 
analysis of DTC websites for accelerated approval products found that 
21 percent of the disclosures used language directly from the approved 
physician labeling, 79 percent of the disclosures used at least some 
medical language, but 27 percent of the websites did not include any 
disclosure that the products attained approval through this pathway 
(Ref. 2). The same analysis found that 84 percent of accelerated 
approval disclosures on DTC websites mentioned the approval basis, 68 
percent mentioned unknown outcomes, and 47 percent mentioned 
confirmatory trials (Ref. 2).
    OPDP recently conducted a general-population study testing the 
disclosure of FDA accelerated approval information on a DTC 
prescription drug website (OMB control number 0910-0872--Experimental 
Study of an Accelerated Approval Disclosure). The study tested a 
control condition with no disclosure; a disclosure based on wording 
used in physician labeling, including more complex or technical 
terminology (physician-labeling disclosure); and a consumer-friendly 
disclosure drafted using simpler language intended to be suited for 
that audience (consumer-friendly disclosure). The disclosures had three 
elements: (1) Approval basis, (2) unknown outcomes, and (3) 
confirmatory trials. The physician labeling disclosure was ``This 
indication is based on response rate. An improvement in survival or 
disease-related symptoms has not been established. Continued approval 
for this indication may be contingent upon verification of clinical 
benefit in subsequent trials.'' The consumer-friendly disclosure was 
``In a clinical trial, [Drug X] returned blood counts to normal. 
However, we currently do not know if [Drug X] helps people live longer 
or feel better. We continue to study [Drug X] in clinical trials to 
learn more about [Drug X]'s benefits.'' We also varied whether the 
physician-labeling and consumer-friendly disclosures were presented 
with low or high prominence (varying the size, color, and location of 
the disclosure). Preliminary results related to the comprehension of 
the disclosures tested in that study suggest that the consumer-friendly 
disclosure helped participants understand information related to the 
drug's accelerated approval, but that participants' understanding was 
low overall.

New Proposed Study

    The purpose of the current project is to replicate and extend our 
prior research through two studies by: (1) Testing the same 
experimental conditions with a different study population (cancer 
survivors and cancer caregivers in study 1) and (2) testing additional 
consumer-friendly disclosures in study 2. Replication is an important 
part of science and, if confirmation of prior results is seen, can

[[Page 31326]]

increase confidence in the results from our first study.
    With regard to proposed Study 1, public comments for FDA's previous 
accelerated approval disclosure study and other similar FDA studies 
have suggested conducting studies with people who have been diagnosed 
with the medical condition or who are caregivers to patients diagnosed 
with the medical condition that the fictitious drug in the study is 
intended to treat. Specifically, public comments on the previous study 
suggested enrolling participants who have been diagnosed with cancer 
(i.e., cancer survivors) or people who have cared for loved ones with 
cancer (i.e., cancer caregivers). Because a number of oncology products 
are granted accelerated approval, cancer survivors and cancer 
caregivers are more likely to seek out or be exposed to promotion for 
accelerated approval products than the general population. They may 
also be more familiar with cancer-related terms and concepts than the 
general population. Study 1 will involve cancer survivors and cancer 
caregivers, a different population than our prior study. It will test 
the ``three element'' version of the disclosure as noted above. We will 
also test the prominence of the disclosure (see table 1).
    With regard to study 2, public comments on the original study 
(Docket No. FDA-2018-N-3138) expressed concern that over-disclosure 
could dissuade consumers from considering accelerated approval 
products. One public comment specifically suggested removing the 
``unknown outcomes'' element in the consumer-friendly and physician-
labeling disclosures. Based on these comments, in study 2, we propose 
testing four versions of the consumer-friendly disclosure (table 2): 
The ``three element'' version of the consumer-friendly disclosure as 
well as three other consumer-friendly disclosures that vary with 
respect to which of these three elements they address. This will allow 
us to evaluate the impact on participants' comprehension of the 
disclosure and perception of the fictitious drug when they view a 
disclosure with only the approval basis, the approval basis plus 
information about the unknown outcomes, the approval basis plus 
information about confirmatory trials, and finally the approval basis 
plus information about both the unknown outcomes and confirmatory 
trials. In study 2, the prominence of all the test conditions will be 
the same and will be the same as the ``high prominence'' version tested 
in study 1.
    We plan to conduct two pretests not longer than 20 minutes, 
administered via internet panel, to pilot the main study procedures. We 
then plan to conduct two main studies not longer than 20 minutes, 
administered via internet panel. For the pretests and main studies, we 
will randomly assign the participants to one of the test conditions 
(see table 1 for the study 1 design and table 2 for the study 2 
design). In both studies, participants will view a website for a 
fictitious oncology prescription drug. After viewing the website, 
participants will complete a questionnaire that assesses whether 
participants noticed the disclosure and their understanding of it, as 
well as perceptions of the drug's risks and benefits. We will also 
measure covariates such as demographics and literacy. The questionnaire 
is available upon request from [email protected].
    For study 1, we hypothesize that participants will be more likely 
to notice the disclosure when it is presented more, rather than less, 
prominently. In turn, we expect that participants' perceptions of the 
drug are more likely to be affected by the disclosure in the high 
prominence condition. We also hypothesize that participants will be 
more likely to notice and understand the disclosure and use it to form 
their perceptions of the drug if they view the consumer-friendly 
language. For study 2, we hypothesize that participants will be more 
likely to understand each accelerated approval concept (i.e., 
confirmatory trials, unknown outcomes) when the disclosure directly 
addresses the concept, compared with when the disclosure does not 
directly address the concept. Finally, we will explore whether the 
inclusion of the concepts of confirmatory trials and unknown outcomes 
in the disclosure affects participants' perceived risk, perceived risk-
benefit tradeoff, perceptions of the website, or information-seeking 
intentions. To test these hypotheses, we will conduct inferential 
statistical tests such as logistic regression and analysis of variance.
    For the pretests and main studies, we plan to recruit individuals 
who report a diagnosis with any cancer (except for certain non-melanoma 
skin cancers) for half the sample and individuals who report being a 
caregiver for someone with a diagnosis with any cancer (except for 
certain non-melanoma skin cancers) for the other half of the sample. We 
will exclude individuals who work for the U.S. Department of Health and 
Human Services or work in the health care, marketing, advertising, or 
pharmaceutical industries. With the sample sizes described below, we 
will have sufficient power to detect small-sized effects in the main 
study (table 3).

                                             Table 1--Study 1 Design
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                                          High prominence          Low prominence                Absent
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Physician-labeling version..........  Condition 1............  Condition 3...........  Condition 5.
Consumer-friendly version...........  Condition 2............  Condition 4...........
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                                             Table 2--Study 2 Design
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                                                       Consumer-friendly disclosure elements
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                                                                                               Approval basis +
                                                       Approval basis +    Approval basis +   unknown outcomes +
                                    Approval basis     unknown outcomes      confirmatory        confirmatory
                                                                                trials              trials
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High prominence.................  Condition 6.......  Condition 7.......  Condition 8.......  Study 1 Condition
                                                                                               2.
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    FDA estimates the burden of this collection of information as 
follows:

                                                     Table 3--Estimated Annual Reporting Burden \1\
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                                                                 Number of
                  Activity                       Number of     responses per   Total annual           Average burden per response           Total hours
                                                respondents     respondent       responses
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Pretest 1 and 2 screener....................           3,600               1               1  0.08 (5 minutes)..........................             288
Study 1 and 2 screener......................          20,600               1               1  0.08 (5 minutes)..........................           1,648
Pretest 1...................................             100               1               1  0.33 (20 minutes).........................              33
Main Study 1................................             630               1               1  0.33 (20 minutes).........................             208
Pretest 2...................................              80               1               1  .33 (20 minutes)..........................              26
Main Study 2................................             400               1               1  0.33 (20 minutes).........................             132
                                             -----------------------------------------------------------------------------------------------------------
    Total...................................  ..............  ..............  ..............  ..........................................           2,335
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES), 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. Beaver J.A., L.J. Howie L.J., L. Pelosof L, et al. ``A 25-Year 
Experience of U.S. Food and Drug Administration Accelerated Approval 
of Malignant Hematology and Oncology Drugs and Biologics: A 
Review.'' JAMA Oncology. 2018; 4(6):849-856. doi:10.1001/
jamaoncol.2017.5618
2. Sullivan H.W., A.C. O'Donoghue, K.T. David, N.J. Patel. 
``Disclosing Accelerated Approval on Direct-to-Consumer Prescription 
Drug Websites.'' Pharmacoepidemiology and Drug Safety. 2018;27:1277-
1280. https://doi.org/10.1002/pds.4664

    Dated: June 2, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-12264 Filed 6-10-21; 8:45 am]
BILLING CODE 4164-01-P