84 FR 20148 - Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Experimental Study of an Accelerated Approval Disclosure

The Food and Drug Administration (FDA) 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).

[Federal Register Volume 84, Number 89 (Wednesday, May 8, 2019)]
[Notices]
[Pages 20148-20151]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2019-09418]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-3138]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Experimental Study of 
an Accelerated Approval Disclosure

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) 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: Fax written comments on the collection of information by June 7, 
2019.

ADDRESSES: To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, 
Fax: 202-395-7285, or emailed to [email protected]. All 
comments should be identified with the OMB control number 0910-NEW and 
title ``Experimental Study of an Accelerated Approval Disclosure.'' 
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.

Experimental Study of an Accelerated Approval Disclosure

OMB Control Number 0910-NEW

I. Background

    Section 1701(a)(4) of the Public Health Service Act (PHS 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 mission of the Office of Prescription Drug Promotion (OPDP) is 
to protect the public health by helping to ensure that prescription 
drug information is truthful, balanced, and accurately communicated so 
that patients and healthcare providers can make informed decisions 
about treatment options. The OPDP's research program supports this 
mission by providing 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 we believe 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 
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 research data through analytical methodology 
development and investigation of sampling and response issues. This 
study falls under the topic of advertising features (content and 
format).
    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 (21 U.S.C. 355(c)) or a 
biological product under section 351(a) of the PHS 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/files/drugs/published/Expedited-Programs-for-Serious-Conditions-Drugs-and-Biologics.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's regulations governing physician labeling for 
prescription drugs, the INDICATIONS AND USAGE section of the FDA-
approved prescribing information (PI) for a drug approved under 
accelerated approval must include a succinct description of the 
limitations of usefulness of the drug and any uncertainty about 
anticipated clinical benefits, with reference to the clinical studies 
section for a discussion of the available evidence (21 CFR

[[Page 20149]]

201.57(c)(2)(i)(B)). Therefore, the PI for accelerated approval 
products typically satisfies this requirement by including a statement 
in the INDICATIONS AND USAGE section about the product's approval under 
the accelerated approval pathway. In a guidance, FDA recommended that 
the INDICATIONS AND USAGE section for drugs approved under accelerated 
approval should generally describe three elements: indication(s), 
limitations of usefulness and clinical benefit uncertainty, and 
continued approval (``Labeling for Human Prescription Drug and 
Biological Products Approved Under the Accelerated Approval Pathway'' 
(January 2019). Available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM390058.pdf.). As 
the PI is intended for healthcare professionals, the information 
related to a drug's accelerated approval generally includes complex 
concepts and sophisticated wording. For example, PIs for accelerated 
approval products include language such as:
     This indication is approved under accelerated approval 
based on [surrogate endpoint]. An improvement in survival or disease-
related symptoms has not been established. Continued approval for this 
indication may be contingent upon verification and description of 
clinical benefit in the confirmatory trial; or
     Approval is based on a reduction in [surrogate endpoint]. 
There are no controlled trials demonstrating a direct treatment benefit 
such as improvement in disease-related symptoms, functioning, or 
increased survival.
    Despite its complexity, sponsors often use this language from the 
PI in direct-to-consumer (DTC) promotional materials for drugs approved 
under accelerated approval. In other cases, DTC promotion of 
accelerated approval products does not communicate the unique 
considerations and potential limitations inherent in the accelerated 
approval process.
    Disclosures may be used to communicate information such as this to 
consumers. Disclosures can include information about scientific and 
clinical data, any residual uncertainty about clinical benefit, and the 
practical utility of scientific and clinical data. These disclosures 
may influence consumer comprehension and affect perception of drug 
risks and benefits. This study will examine the presence, wording, and 
prominence of a disclosure communicating information related to the 
drug's accelerated approval in DTC promotional materials. This 
information includes the use of surrogate or intermediate clinical 
endpoints to support approval, the uncertainty about the relationship 
of the surrogate or intermediate clinical endpoint to the predicted 
clinical benefit, and the need for confirmatory trials.
    We plan to conduct one pretest not longer than 20 minutes, 
administered via internet panel, to test the experimental manipulations 
and pilot the main study procedures. After implementing any lessons 
learned from the pilot, we plan to conduct one main study not longer 
than 20 minutes, administered via internet panel. For the pretest and 
main study, we will randomly assign the participants to one of the test 
conditions (see table 1 for the study design). We have chosen to focus 
on oncology products because cancer is a life-threatening illness, and 
many oncology products are granted accelerated approval. Moreover, DTC 
promotion of oncology drugs is common. In the study, participants will 
view a website for a fictional oncology prescription drug. After 
viewing the website, participants will complete a questionnaire that 
assesses whether participants noticed the disclosure and their 
interpretation 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].
    We will vary the presence and prominence of the disclosure (e.g., 
size, color, and location). 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 will vary whether 
the disclosure is written in consumer-friendly language or uses 
language, in use by many sponsors, which is the same as or similar to 
that directed at healthcare professionals in FDA-approved prescription 
drug labeling for accelerated approval products. The consumer-friendly 
version of the accelerated approval disclosure will be based on 
consumer feedback elicited in focus groups conducted prior to the 
pretest (approved under OMB control number 0910-0695). The physician 
labeling version of the accelerated approval disclosure will be drawn 
from FDA-approved physician labeling. We 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. To test these hypotheses, we will conduct 
inferential statistical tests such as logistic regression and analysis 
of variance.

                                              Table 1--Study Design
----------------------------------------------------------------------------------------------------------------
                                                                       High
                                                                    prominence    Low prominence      Absent
----------------------------------------------------------------------------------------------------------------
Physician Labeling version......................................
Consumer-friendly version.......................................
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    We will recruit a general population sample of adult volunteers 18 
years of age or older. We will exclude individuals who work for the 
U.S. Department of Health and Human Services or work in the healthcare, 
marketing, advertising, or pharmaceutical industries. We will use 
health literacy quotas to ensure that our sample includes participants 
with a range of health literacy skills. With the sample sizes described 
below, we will have sufficient power to detect small-sized effects in 
the main study (table 2).
    In the Federal Register of October 17, 2018 (83 FR 52478), FDA 
published a 60-day notice requesting public comment on the proposed 
collection of information. FDA received four submissions that were PRA-
related. Within those submissions, FDA received multiple comments, 
which the Agency has addressed below.
    (Comment 1) One comment suggested that the study does not evaluate 
the extent to which patients understand accelerated approval, 
``including the serious and life-threatening nature of the disease, the 
fact that FDA determined that the product is likely to provide a 
meaningful advantage over available therapy, the fact that the

[[Page 20150]]

product likely addresses a significant unmet medical need, and that the 
accelerated approval has yet to be confirmed with additional data.'' 
The comment suggests updating Q12, Q13, and Q18 to reflect this 
context.
    (Response) We will begin the study by giving participants 
information about acute lymphoblastic leukemia, which includes its 
serious and life-threatening nature, to put the accelerated approval of 
the drug product in the appropriate context. Questions 3-9 assess 
participants' understanding of the accelerated approval concepts 
conveyed in the disclosure. The concepts in the disclosure align with 
the elements recommended by FDA to describe accelerated approval 
products and information currently seen in DTC promotion (Ref. 2). 
Questions 12, 13, and 18 are designed to measure participants' 
perceptions of the drug's risks.
    (Comment 2) One comment suggested that the proposed disclosure 
language, ``we currently do not know if Drug X helps people live longer 
or feel better'' should be replaced with ``we currently do not know if 
Drug X helps to minimize progression of disease and improve quality of 
life.'' The comment noted that the proposed language may be simplistic 
and inaccurate because ``feel better'' is subjective and may be 
irrelevant for cancer treatments.
    (Response) In many cases, the available data for accelerated 
approval products do provide information about disease progression, 
without providing information on overall survival (i.e., living 
longer). Therefore, we do not believe that replacing ``live longer'' 
with ``minimizing progression of disease'' makes the disclosure more 
accurate or consumer-friendly. In addition, based on our focus group 
testing, we believe that ``feel better'' is a consumer-friendly way to 
discuss improvements in symptoms or quality of life. We disagree that 
this is an irrelevant outcome for cancer patients.
    (Comment 3) One comment stated that Q26 (Perspective Taking Scale) 
does not appear necessary.
    (Response) We included the Perspective Taking Scale as a potential 
moderator. Participants will be drawn from the general public, and we 
will ask them to imagine that someone close to them was recently 
diagnosed with the relevant medical condition. Participants' ability to 
identify with a different perspective might affect how well they are 
able to do this. We will evaluate the usefulness of this measure in the 
pretest and drop it from the main study if it does not apply.
    (Comment 4) One comment recommended studying another consumer-
friendly disclosure in place of the physician labeling version of the 
disclosure. In addition, this comment recommended that the consumer-
friendly disclosure not mention unknown outcomes (i.e., ``we currently 
do not know if Drug X helps people live longer or feel better.'').
    (Response) We plan to study the physician labeling version of the 
disclosure because sponsors currently use this language to explain 
accelerated approval in DTC promotion (Ref. 2). We plan to include a 
statement about unknown outcomes in the disclosure because it is one of 
the elements recommended by FDA to describe accelerated approval 
products, and it is present in currently used accelerated approval 
disclosures (Ref. 2). We are in support of additional research that 
would study alternate consumer-friendly versions.
    (Comment 5) One comment requested clarification on the execution of 
the prominence conditions, in particular regarding its proximity to the 
indication.
    (Response) The disclosure will be presented in direct conjunction 
with the indication in both prominence conditions. In the high 
prominence condition, the disclosure will also be presented along with 
the largest claim.
    (Comment 6) Three comments requested access to the study stimuli.
    (Response) We have described the purpose of the study, the design, 
the population of interest, and have provided the questionnaire to 
numerous individuals upon request. We provided the disclosure language 
in the questionnaire. 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 7) One comment requested that we clarify the primary 
measure of the study.
    (Response) Our hypotheses are based on noticing the disclosure 
(Q20), understanding the disclosure (Q3-Q9), and perceptions (Q10-Q17).
    (Comment 8) One comment asked why items Q20 and Q21 come after 
items Q7-Q19.
    (Response) Items Q7-Q19 are designed to measure participants' 
reaction to the experimental condition to which they were assigned. 
Items Q20 and Q21 show the disclosure to all participants (regardless 
of experimental condition) and ask them to respond to it.
    (Comment 9) One comment questioned the utility of Q19-B.
    (Response) We agree with this concern and have deleted this item.
    (Comment 10) One comment stated a concern that an accelerated 
approval disclosure could cause undue apprehension and deter people who 
might otherwise benefit from seeking treatment advice about accelerated 
approval products. Based on this concern, the comment suggested adding 
questions about whether participants would seek information regarding 
potential risks or discuss the accelerated approval status with a 
healthcare professional.
    (Response) The current study is intended to gather data that will 
help us understand how accelerated approval disclosures may impact 
consumer perception of an accelerated approval drug product. In a 
content analysis of accelerated approval product websites, we found 
that 73 percent currently include some form of a disclosure already 
(Ref. 2). Therefore, it is important to study what effect these 
disclosures may have. We will measure participants' perceptions of the 
drug's benefits and risks. In addition, we have expanded our intention 
question to also measure intentions to suggest a loved one ask their 
doctor about the drug's risks, benefits, and FDA approval.
    (Comment 11) One comment suggested that promotional materials are 
not the best venue for providing information about prescription drugs, 
given the role of healthcare professionals in discussing and 
prescribing treatments. Based on this, the comment suggested modifying 
the study to focus on prescriber-patient interactions rather than DTC 
promotion.
    (Response) Consumers often wish to participate in shared decision-
making with healthcare professionals when selecting prescription drugs 
and may request specific prescription drugs from their healthcare 
professionals based on promotions they have seen in the marketplace. 
Because information consumers receive through DTC prescription drug 
promotion can impact these requests, it is important to investigate how 
the information in prescription drug promotional pieces impacts 
consumer attention, understanding, and perceptions.
    (Comment 12) One comment noted that, in real-world conditions, 
consumers do not choose an accelerated approval product in a vacuum. 
This comment requested that we provide participants with information on 
the limited availability and/or effectiveness of alternative 
treatments.

[[Page 20151]]

    (Response) We acknowledge that accelerated approval products often 
constitute the only treatment option or one of a limited number of 
treatment options available to patients. We revised the questionnaire 
to include information for participants in this study about the 
treatment landscape for the disease.
    (Comment 13) One comment recommends enrolling a diversity of 
participants across demographic categories and geographic locations. 
They suggest screening for pretest participants, individuals who have 
recently participated in prescription drug research, and individuals 
with prior use of oncology products or accelerated approval products.
    (Response) Participants will be internet panel members. We will use 
soft quotas to ensure recruitment of a low health literacy population 
as well as a demographically diverse set of participants. Pretest 
participants will not be allowed to participate in the main study. We 
added questionnaire items asking participants whether they have been 
diagnosed with cancer, and if so whether they have ever taken 
prescription drugs, and specifically accelerated approval products, for 
cancer.
    (Comment 14) One comment noted that participants may pay more 
attention to information presented in a study, including claims 
designed to be intentionally misleading, and asked what efforts we will 
take to avoid response bias.
    (Response) The study design does not include intentionally 
misleading claims. Based on previous research with DTC prescription 
drug websites, we expect the median time spent on the study stimuli to 
be under a minute to 2 minutes (Ref. 3). In general, we attempt to 
minimize response bias by following best practices, such as keeping the 
survey length short and cognitive-testing and pretesting the questions 
to make sure they are clearly written.
    (Comment 15) One comment requested that the screener and consent 
form be made available.
    (Response) The screener and consent form are available as part of 
the information collection submission to the OMB.
    (Comment 16) One comment noted that the wording of Q4 and Q9 could 
lead participants toward a specific response.
    (Response) These questions are designed to measure whether 
participants processed the information in the disclosure. Thus, Q4 asks 
about the unknown outcome information from the disclosure, and Q9 asks 
about the continuing research information from the disclosure. Because 
these are not meant to be questions about perceptions, we have changed 
the wording of Q4 to clarify that we are asking about what the website 
said, rather than what they might think. We will evaluate these items 
in cognitive interview and pretesting.
    (Comment 17) One comment recommended adding intermediate response 
values for Q10-Q17 and Q24-Q26.
    (Response) We have added intermediate response values for these 
items, with the exception of Q26, the Perspective Taking Scale, to be 
consistent with its previous use.
    FDA estimates the burden of this collection of information as 
follows:

                                                     Table 2--Estimated Annual Reporting Burden \1\
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                                                                   No. of
                   Activity                        No. of       responses per   Total annual          Average burden per response           Total Hours
                                                 respondents     respondent       responses
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Pretest screener.............................             916               1               1  0.08 (5 minutes).........................           73.28
Study screener...............................           1,507               1               1  0.08 (5 minutes).........................          120.56
Pretest......................................             385               1               1  0.33 (20 minutes)........................          127.05
Main Study...................................             633               1               1  0.33 (20 minutes)........................          208.89
                                              ----------------------------------------------------------------------------------------------------------
    Total....................................  ..............  ..............  ..............  .........................................          529.78
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

II. References

    The following references are on display with the Dockets Management 
Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 
1061, Rockville, MD 20852, and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; these are not 
available electronically at https://www.regulations.gov as these 
references are copyright protected. Some may be available at the 
website address, if listed. 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. Pelosof, 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, 4(6):849-856, 2018. doi:10.1001/
jamaoncol.2017.5618.
2. Sullivan H.W., A.C. O'Donoghue, K.T. David, et al., ``Disclosing 
Accelerated Approval on Direct-to-Consumer Prescription Drug 
websites.'' Pharmacoepidemiology and Drug Safety, 27:1277-1280, 
2018. https://doi.org/10.1002/pds.4664.
3. Sullivan H.W., A.C. O'Donoghue, D.J. Rupert, et al., ``Placement 
and Format of Risk Information on Direct-to-Consumer Prescription 
Drug Websites.'' Journal of Health Communication, 22:171-181, 2017.


    Dated: May 2, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-09418 Filed 5-7-19; 8:45 am]
 BILLING CODE 4164-01-P