[Federal Register Volume 79, Number 115 (Monday, June 16, 2014)]
[Notices]
[Pages 34315-34317]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-13907]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-N-0731]


Methodological Considerations in Evaluation of Cancer as an 
Adverse Outcome Associated With Use of Non-Oncological Drugs and 
Biological Products in the Postapproval Setting; Public Meeting; 
Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comments.

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    The Food and Drug Administration (FDA), in collaboration with the 
National Cancer Institute (NCI), is announcing a public meeting 
entitled ``Methodological Considerations in Evaluation of Cancer as an 
Adverse Outcome Associated With Use of Non-Oncological Drugs and 
Biological Products in the Postapproval Setting.'' The purpose of the 
public meeting is to engage in constructive dialogue and information 
sharing among regulators, researchers, the pharmaceutical industry, 
public health agencies, health care providers, and the general public 
concerning challenges in designing and implementing postapproval 
studies to evaluate the risk of cancer associated with use of non-
oncological drugs and biological products. The input from this meeting 
and public docket will be used to inform the Agency on best study 
design and methodological options to consider when evaluating cancer 
risk in the postapproval setting.
    Dates and Time: The public meeting will be held on September 10, 
2014, from 8 a.m. to 5 p.m., and September 11, 2014, from 8 a.m. to 5 
p.m.
    Location: The public meeting will be held at The DoubleTree by 
Hilton Hotel Washington DC--Silver Spring, The Maryland Ballroom, 8727 
Colesville Rd., Silver Spring, MD 20910 (Metro: Silver Spring Station 
on the Red Line).
    Contact Person: Paul Tran, Center for Drug Evaluation and Research, 
Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, 
MD 20993-0002, 301-796-9029, FAX: 301-796-9832, [email protected].
    Registration and Requests for Oral Presentations: Registration is 
free and available on a first-come, first-served basis. You must 
register online by August 27, 2014. Seating is limited, so register 
early. FDA may limit the number of participants from each organization. 
If time and space permit, onsite registration on the day of the meeting 
will be available. To register for this meeting, please visit FDA's 
Drugs News & Events--Meetings, Conferences, & Workshops calendar at 
http://www.fda.gov/Drugs/NewsEvents/ucm132703.htm and select this 
meeting from the events list. If you need special accommodations due to 
a disability, please contact Paul Tran (see Contact Person) by 
September 3, 2014. Those without Internet access should contact Paul 
Tran to register.
    This meeting includes a public comment session. If you would like 
to present at the meeting on topics related to challenges in designing 
and implementing postapproval studies to evaluate the risk of cancer 
associated with use of non-oncological drugs and biological products, 
please identify during registration the topic(s) you will address (see 
section II).
    FDA will do its best to accommodate requests to speak. FDA urges 
individuals and organizations with common interests to coordinate and 
give a joint, consolidated presentation. Following the close of 
registration, FDA will allot time for each presentation and notify 
presenters by September 3, 2014.

[[Page 34316]]

Do not present or distribute commercial or promotional material during 
the meeting. Registered presenters should check in before the meeting.
    Comments: FDA is holding this meeting to seek input on the study 
design and methodological options for conducting postapproval studies 
to evaluate cancer as an adverse outcome associated with use of non-
oncological drugs and biological products. FDA is soliciting from 
interested persons electronic or written comments on all aspects of the 
meeting topics through October 9, 2014.
    Attendees and non-attendees may submit electronic comments to 
http://www.regulations.gov. Submit written comments to the Division of 
Dockets Management (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD 20852. Send only one set of 
comments. When sending comments, please include the docket number from 
the heading of this notice. In addition, when addressing specific 
topics (see section II), please identify the topic. Received comments 
may be viewed in the Division of Dockets Management between 9 a.m. and 
4 p.m., Monday through Friday, and will be posted to the docket at 
http://www.regulations.gov.
    Transcripts: After the meeting, FDA will post a transcript at 
http://www.regulations.gov. The transcript may be viewed at the 
Division of Dockets Management (see Comments). A transcript will also 
be available in either hardcopy or on CD-ROM upon submission of a 
Freedom of Information request. Send requests to the Division of 
Freedom of Information (ELEM-1029), Food and Drug Administration, 12420 
Parklawn Dr., Element Bldg., Rockville, MD 20857.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is holding this meeting to seek input from industry, academia, 
public health agencies, the clinical community, and other stakeholders 
regarding the study design and methodological options for conducting 
studies to evaluate cancer as an adverse outcome associated with use of 
non-oncological drugs and biological products in the postapproval 
setting.
    Questions about whether a drug causes or influences cancer 
development and how this cancer risk can be evaluated are frequent 
concerns posed to FDA. Cancer signals can arise from premarket non-
clinical and clinical trial data, and also from spontaneous adverse 
event reports or other studies conducted following a drug's approval. 
Unfortunately, further evaluation of these cancer signals is hindered 
by methodological limitations of tools and data available in the 
postapproval setting, particularly in light of the often complex 
exposure patterns and expected long latency of certain cancer outcomes. 
In the preapproval setting, randomized controlled trials (RCTs) are 
considered the gold standard in evaluating drug efficacy, and can 
evaluate frequently occurring and short-latency adverse events. 
However, due to certain limitations, RCTs are not best suited to 
identify the occurrence of cancer as an adverse outcome associated with 
drug treatment, although cancer events observed in trials raise 
concerns. Preapproval RCTs have important limitations, such as use of 
restricted populations, limited number of participants, as well as 
short duration and followup time. Postapproval studies, frequently 
observational, better reflect real-world-use patterns and capture the 
clinical experience for a larger number of individuals over time. In 
theory, these studies are better positioned to evaluate rare and 
longer-latency drug safety signals, including cancer signals. In 
practice, however, evaluating drug-related cancer outcomes using 
observational data is hampered by important methodological limitations, 
including difficulties in determining the timing of the outcome 
occurrence accurately, difficulties in identifying the biologically 
relevant period of risk, and challenges in handling complex exposure 
patterns over time, among others.
    Given the many methodological challenges in the postmarketing 
evaluation of adverse cancer outcomes associated with use of non-
oncological products and current gaps in knowledge, FDA, in 
collaboration with NCI, is sponsoring a public meeting to seek input 
from industry, academia, public health agencies, the clinical 
community, and other stakeholders.
    The meeting will include multiple sessions over 2 days.

II. Scope of the Meeting

    The objective of the meeting is to engage researchers, industry, 
public health agencies, health care providers, and the public through 
presentations and panel discussions on the following topics:
    Topic 1: Determination of exposure and identification of relevant 
risk window. The ability to accurately capture complex drug-use 
patterns over a period of time, to determine the most appropriate 
exposure metric(s), and to identify the most biologically relevant risk 
periods are essential elements in the appropriate postapproval 
evaluation of cancer-related outcomes associated with use of non-
oncological drugs and biological products. There is currently no 
consensus on how these elements should be considered in postapproval 
studies that evaluate cancer outcomes. Discussions will explore 
methodologies for determining informative exposure metric(s), 
thresholds, latency period, and length of followup. These discussions 
will be based on current knowledge of carcinogenesis, potential 
underlying biological mechanisms, and particular types of cancers 
(according to site or histology). Given uncertainties around defining 
some of these metrics, discussions may consider strategies beyond 
testing of hypotheses, including the use of exploratory hypotheses and 
sensitivity analyses, as well as consideration of scenarios under which 
postapproval studies are unlikely to be informative.
    Topic 2: Identification of cancer-related outcome(s). The insidious 
nature of cancer events makes identification and timing-of-event 
occurrence challenging. Discussions will focus on relevant 
methodologies to identify cancer-related outcomes, as well as 
considerations regarding the challenges involved in identifying the 
sequence of symptoms that eventually lead to an accurate cancer 
diagnosis, a sequence that may be initiated before or during drug 
exposure.
    Topic 3: Identification of population/data source. Identifying the 
relevant characteristics of the data or population source is crucial in 
conducting and interpreting postapproval evaluations of cancer signals. 
Discussions will focus on the essential characteristics of population/
data source (e.g. administrative databases, registries, clinical 
encounters, surveys/interviews); the ability to appropriately capture 
medical history over time; and other information relevant to the 
evaluation of cancer outcomes, sample size, and participant followup.
    Topic 4: Current thinking on cancer biology to inform epidemiology 
study design. It is noteworthy that recommendations for postapproval 
study designs to date have been based on the concept that cancer 
develops over a period of time, long after initiating drug treatment 
(long latency period). Nonetheless, several cancer-related signals have 
been observed during preapproval RCTs of non-oncological therapies, 
trials which typically have short duration of followup. Discussions 
will focus on the current thinking of potential biological mechanism(s) 
underlying purported drug-related increase in initiating, promoting, or 
detecting cancerous

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tumors, with particular consideration given to scenarios where cancer 
signals arise at any time following drug exposure. Discussions will 
also focus on cancer biology (and the different types of tumors) to 
inform postapproval evaluation of cancer signals and to better identify 
the most relevant exposure metric and risk windows.
    Information about this meeting, including registration and the 
agenda, will be posted at http://www.fda.gov/Drugs/NewsEvents/ucm132703.htm as it becomes available.

    Dated: June 10, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-13907 Filed 6-13-14; 8:45 am]
BILLING CODE 4164-01-P