80 FR 27326 - Dose Finding of Small Molecule Oncology Drugs; Public Workshop

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 80, Issue 92 (May 13, 2015)

Page Range		27326-27327
FR Document		2015-11536
Federal Register, Volume 80 Issue 92 (Wednesday, May 13, 2015)
[Federal Register Volume 80, Number 92 (Wednesday, May 13, 2015)]
[Notices]
[Pages 27326-27327]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2015-11536]



[[Page 27326]]

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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

[[Page 27327]]

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
27326 Federal Register / Vol. 80, No. 92 / Wednesday, May 13, 2015 / Notices

DEPARTMENT OF HEALTH AND day of the public workshop will be viewed at the Division of Dockets
HUMAN SERVICES provided beginning at 7 a.m. Management (see Comments). A
If you need special accommodations transcript will also be available in either
Food and Drug Administration due to a disability, please contact the hardcopy or on CD–ROM, after
Washington Court Hotel no later than submission of a Freedom of Information
[Docket No. FDA–2015–N–1306]
May 14, 2015. request. Written requests are to be sent
Dose Finding of Small Molecule To register for the public workshop, to the Division of Freedom of
Oncology Drugs; Public Workshop visit https://www.surveymonkey.com/s/ Information (ELEM–1029), Food and
WTM2Z57. Please provide complete Drug Administration, 12420 Parklawn
AGENCY: Food and Drug Administration, contact information for each attendee, Dr., Element Bldg., Rockville, MD
HHS. including name, title, affiliation, email, 20857. A link to the transcript will also
ACTION: Notice of public workshop. and telephone number. Registrants will be available approximately 45 days after
receive confirmation after they have the public workshop at http://
The Food and Drug Administration been accepted. Registrants will be www.fda.gov/MedicalDevices/
(FDA), in cosponsorship with the notified if they are on a waiting list. NewsEvents/WorkshopsConferences/
American Association for Cancer Streaming Audiocast of the Public default.htm. Select this public
Research (AACR), is announcing a Workshop: This public workshop will workshop from the posted events list.
public workshop entitled ‘‘Dose Finding also be available via audiocast. Persons SUPPLEMENTARY INFORMATION:
of Small Molecule Oncology Drugs.’’ interested in accessing the audiocast
The purpose of this 2-day workshop is must register online at https:// I. Background
to provide an interdisciplinary forum to www.surveymonkey.com/s/WTM2Z57. Since the approval of imatinib in
discuss the best practices of dose FDA has verified the Web site addresses 2001, FDA has approved 26 small
finding and dose selection for small in this document, but FDA is not molecule kinase inhibitors for the
molecule kinase inhibitors developed responsible for any subsequent changes treatment of oncology indications. For
for oncology indications. The goal is to to the Web sites after this document the first several small molecule kinase
foster robust scientific discussion to publishes in the Federal Register. Early inhibitors in development, it was
promote a movement away from the registration is recommended because common to see multiple dose-finding
conventional 3+3 dose escalation trial audiocast connections are limited. trials that evaluated multiple dose levels
design and move toward innovative Organizations are requested to register and dosing schedules. As additional
designs that can potentially incorporate all participants but to listen using one small molecule kinase inhibitors
key clinical, pharmacologic, and connection per location. After entered clinical trials and the familiarity
pharmacometric data and, when registration, participants will be sent with this class of drugs increased, the
appropriate, nonclinical information to technical system requirements and number of dose-finding trials for each
guide dose selection. Ideally, this connection access information after May compound reduced in number.
workshop will propel a movement 14, 2015. Although this may appear to be a
toward integrating dose finding into the Comments: FDA is holding this public product of increased efficiency in trial
entire life cycle of product development workshop to provide an design and dose finding, proper doses or
as opposed to confining it to the Phase interdisciplinary forum to discuss the dose ranges appear to not have been
1, first-in-human trial based on short- best practices of dose finding and dose identified for approved products, as
term safety measures. selection for small molecule kinase evident by the high prevalence of dose
Date and Time: The public workshop inhibitors developed for oncology reductions observed in registration trials
will be held on May 18 and 19, 2015, indications. To permit the widest and the high frequency of postmarketing
from 8 a.m. to 5 p.m. possible opportunity to obtain public requirements to study alternative doses.
Location: The public workshop will comment, FDA is soliciting either In some cases, critical cross-disciplinary
be held at the Washington Court Hotel, electronic or written comments on all information does not appear to be
525 New Jersey Ave. NW., Washington, aspects of the public workshop topics. integrated into the dose-finding process.
DC 20001, 202–628–2100. The deadline for submitting comments Given the recent history of approvals
Contact Persons: Rasika Kalamegham, related to this public workshop is June based on the results of early phase trials
American Association for Cancer 18, 2015. driven by extraordinary efficacy data,
Research, 1425 K St. NW., Washington, Regardless of attendance at the public the incentive for conducting rigorous
DC 20005, 267–765–1029, workshop, you may submit either dose-finding trials may not be overtly
Rasika.Kalamegham@aacr.org; and electronic comments regarding this apparent. However, the increasing need
Christine Lincoln, Office of Hematology document to http://www.regulations.gov for the development of combination
and Oncology Products, Center for Drug or written comments to the Division of therapy due to resistance to
Evaluation and Research, Food and Dockets Management (HFA–305), Food monotherapy and poor tolerance of
Drug Administration, 10903 New and Drug Administration, 5630 Fishers approved dosing regimens underscores
Hampshire Ave., Silver Spring, MD, Lane, Rm. 1061, Rockville, MD 20852. It the need for a more efficient process of
20993–0002, Christine.Lincoln@ is only necessary to send one set of dose selection in the early stages of
fda.hhs.gov. comments. Identify comments with the study design.
Registration: Registration is free and docket number found in brackets in the
available on a first-come, first-served heading of this document. Received II. Summary
asabaliauskas on DSK5VPTVN1PROD with NOTICES

basis. You must register online by May comments may be seen in the Division FDA’s Center for Drug Evaluation and
14, 2015, 5 p.m. Registration will be of Dockets Management between 9 a.m. Research and the AACR agree to
handled through AACR. Early and 4 p.m., Monday through Friday, and cosponsor a workshop focusing on
registration is recommended because will be posted to the docket at http:// providing a forum for discussion of best
facilities are limited and, therefore, FDA www.regulations.gov. practices on dose finding of small
may limit the number of participants Transcript: As soon as a transcript is molecule oncology drugs. The workshop
from each organization. If time and available, it will be accessible at will be held May 18 and 19, 2015, and
space permits, onsite registration on the http://www.regulations.gov. It may be is expected to include between 10 to 13

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Document Created: 2015-12-16 07:46:44
Document Modified: 2015-12-16 07:46:44
Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Notices
Action		Notice of public workshop.
FR Citation		80 FR 27326
80 FR 27326 - Dose Finding of Small Molecule Oncology Drugs; Public Workshop

DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration

Federal Register Volume 80, Issue 92 (May 13, 2015)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
