[Federal Register Volume 80, Number 92 (Wednesday, May 13, 2015)]
[Notices]
[Pages 27326-27327]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-11536]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2015-N-1306]


Dose Finding of Small Molecule Oncology Drugs; Public Workshop

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public workshop.

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    The Food and Drug Administration (FDA), in cosponsorship with the 
American Association for Cancer Research (AACR), is announcing a public 
workshop entitled ``Dose Finding of Small Molecule Oncology Drugs.'' 
The purpose of this 2-day workshop is to provide an interdisciplinary 
forum to discuss the best practices of dose finding and dose selection 
for small molecule kinase inhibitors developed for oncology 
indications. The goal is to foster robust scientific discussion to 
promote a movement away from the conventional 3+3 dose escalation trial 
design and move toward innovative designs that can potentially 
incorporate key clinical, pharmacologic, and pharmacometric data and, 
when appropriate, nonclinical information to guide dose selection. 
Ideally, this workshop will propel a movement toward integrating dose 
finding into the entire life cycle of product development as opposed to 
confining it to the Phase 1, first-in-human trial based on short-term 
safety measures.
    Date and Time: The public workshop will be held on May 18 and 19, 
2015, from 8 a.m. to 5 p.m.
    Location: The public workshop will be held at the Washington Court 
Hotel, 525 New Jersey Ave. NW., Washington, DC 20001, 202-628-2100.
    Contact Persons: Rasika Kalamegham, American Association for Cancer 
Research, 1425 K St. NW., Washington, DC 20005, 267-765-1029, 
[email protected]; and Christine Lincoln, Office of Hematology 
and Oncology Products, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 
20993-0002, [email protected].
    Registration: Registration is free and available on a first-come, 
first-served basis. You must register online by May 14, 2015, 5 p.m. 
Registration will be handled through AACR. Early registration is 
recommended because facilities are limited and, therefore, FDA may 
limit the number of participants from each organization. If time and 
space permits, onsite registration on the day of the public workshop 
will be provided beginning at 7 a.m.
    If you need special accommodations due to a disability, please 
contact the Washington Court Hotel no later than May 14, 2015.
    To register for the public workshop, visit https://www.surveymonkey.com/s/WTM2Z57. Please provide complete contact 
information for each attendee, including name, title, affiliation, 
email, and telephone number. Registrants will receive confirmation 
after they have been accepted. Registrants will be notified if they are 
on a waiting list.
    Streaming Audiocast of the Public Workshop: This public workshop 
will also be available via audiocast. Persons interested in accessing 
the audiocast must register online at https://www.surveymonkey.com/s/WTM2Z57. FDA has verified the Web site addresses in this document, but 
FDA is not responsible for any subsequent changes to the Web sites 
after this document publishes in the Federal Register. Early 
registration is recommended because audiocast connections are limited. 
Organizations are requested to register all participants but to listen 
using one connection per location. After registration, participants 
will be sent technical system requirements and connection access 
information after May 14, 2015.
    Comments: FDA is holding this public workshop to provide an 
interdisciplinary forum to discuss the best practices of dose finding 
and dose selection for small molecule kinase inhibitors developed for 
oncology indications. To permit the widest possible opportunity to 
obtain public comment, FDA is soliciting either electronic or written 
comments on all aspects of the public workshop topics. The deadline for 
submitting comments related to this public workshop is June 18, 2015.
    Regardless of attendance at the public workshop, you may submit 
either electronic comments regarding this document to http://www.regulations.gov or written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852. It is only necessary to send one set of 
comments. Identify comments with the docket number found in brackets in 
the heading of this document. Received comments may be seen 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.
    Transcript: As soon as a transcript is available, it will be 
accessible at http://www.regulations.gov. It may be viewed at the 
Division of Dockets Management (see Comments). A transcript will also 
be available in either hardcopy or on CD-ROM, after submission of a 
Freedom of Information request. Written requests are to be sent to the 
Division of Freedom of Information (ELEM-1029), Food and Drug 
Administration, 12420 Parklawn Dr., Element Bldg., Rockville, MD 20857. 
A link to the transcript will also be available approximately 45 days 
after the public workshop at http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/default.htm. Select this public 
workshop from the posted events list.

SUPPLEMENTARY INFORMATION:

I. Background

    Since the approval of imatinib in 2001, FDA has approved 26 small 
molecule kinase inhibitors for the treatment of oncology indications. 
For the first several small molecule kinase inhibitors in development, 
it was common to see multiple dose-finding trials that evaluated 
multiple dose levels and dosing schedules. As additional small molecule 
kinase inhibitors entered clinical trials and the familiarity with this 
class of drugs increased, the number of dose-finding trials for each 
compound reduced in number. Although this may appear to be a product of 
increased efficiency in trial design and dose finding, proper doses or 
dose ranges appear to not have been identified for approved products, 
as evident by the high prevalence of dose reductions observed in 
registration trials and the high frequency of postmarketing 
requirements to study alternative doses. In some cases, critical cross-
disciplinary information does not appear to be integrated into the 
dose-finding process. Given the recent history of approvals based on 
the results of early phase trials driven by extraordinary efficacy 
data, the incentive for conducting rigorous dose-finding trials may not 
be overtly apparent. However, the increasing need for the development 
of combination therapy due to resistance to monotherapy and poor 
tolerance of approved dosing regimens underscores the need for a more 
efficient process of dose selection in the early stages of study 
design.

II. Summary

    FDA's Center for Drug Evaluation and Research and the AACR agree to 
cosponsor a workshop focusing on providing a forum for discussion of 
best practices on dose finding of small molecule oncology drugs. The 
workshop will be held May 18 and 19, 2015, and is expected to include 
between 10 to 13

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panelists and speakers (including a moderator) per each of the 4 
sessions and will be open to the public.

III. Purpose

    The purpose of this 2-day workshop is to provide an 
interdisciplinary forum to discuss the best practices of dose finding 
and dose selection for small molecule kinase inhibitors developed for 
oncology indications. The goal is to foster robust scientific 
discussion to promote a movement away from the conventional 3+3 dose 
escalation trial design and move toward adaptive designs that can 
potentially incorporate key clinical, pharmacologic, and pharmacometric 
data and, when appropriate, nonclinical information to guide dose 
selection. Ideally, this workshop will propel a movement toward 
integrating dose finding into the entire life cycle of product 
development as opposed to confining it to the Phase 1, first-in-human 
trial based on short-term safety measures.

IV. Goals and Scope

    1. To identify key best practices in the nonclinical evaluation of 
a compound, including, but not limited to, selectivity, pharmacology, 
secondary pharmacology, and toxicology.
    2. To assess whether nonclinical information can be incorporated 
into the statistical assumptions of an adaptive dose-finding trial.
    3. To discuss the best practices of integrating human 
pharmacokinetic and pharmacometric data, including drug interaction, 
when appropriate, into dose-finding studies.
    4. To assess how drug exposure can be integrated into the 
statistical assumptions of an adaptive dose-finding trial and to assess 
whether evolving exposure data can be adapted into an ongoing trial.
    5. To discuss barriers in moving away from 3+3 designs toward 
adaptive designs and to encourage creative dose-finding trial designs 
that can replace the conventional 3+3 dose-finding study, where 
appropriate.
    6. To shift from conducting a large single-arm drug trial with the 
maximum tolerated dose based on a 28-day window to identify tolerable, 
biologically effective doses for confirmatory trials through prudent 
search of doses based on safety, efficacy, and patient tolerability.
    7. To discuss potential regulatory implications of dose-finding 
studies, including, but not limited to, product labeling of dose 
ranges, dose titration, and postmarketing studies.

    Dated: May 6, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-11536 Filed 5-12-15; 8:45 am]
 BILLING CODE 4164-01-P