Guidance for Industry on Clozapine Tablets: In Vivo Bioequivalence and In Vitro Dissolution Testing; Availability, 35447-35448 [05-12039]
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Federal Register / Vol. 70, No. 117 / Monday, June 20, 2005 / Notices
State Enforcement Notifications—21
CFR 100.2(d) (OMB Control Number
0910–0275)—Extension
Section 310(b) of the Federal Food,
Drug, and Cosmetic Act (the act) (21
U.S.C. 337(b)) authorizes States to
enforce certain sections of the act in
their own names, but provides that
States must notify FDA before doing so.
Section 100.2(d) (21 CFR 100.2 (d)) sets
forth the information that a State must
provide to FDA in a letter of notification
when it intends to take enforcement
action under the act against a particular
food located in the State. The
information required under § 100.2(d)
will enable FDA to identify the food
against which the State intends to take
action and advise the State whether
Federal action has been taken against it.
With certain narrow exceptions, Federal
enforcement action precludes State
action under the act.
FDA estimates the burden of this
collection of information as follows:
TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1
21 CFR Section
100.2(d)
1
1There
Total Annual
Responses
1
1
Hours Per
Response
10
Total Hours
10
are no capital costs or operating and maintenance costs associated with this collection of information.
The reporting burden for § 100.2(d) is
insignificant because enforcement
notifications are seldom used by States.
During the last 3 years, FDA has not
received any enforcement notifications.
Since the enactment of section 403A(b)
of the act (21 U.S.C. 343–1(b)) as part of
the Nutrition Labeling and Education
Act of 1990, FDA has received only a
few enforcement notifications. Although
FDA believes that the burden will be
insignificant, it believes these
information collection provisions
should be extended to provide for the
potential future need of a State
government to submit enforcement
notifications informing FDA when it
intends to take enforcement action
under the act against a particular food
located in the State.
Dated: June 14, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05–12055 Filed 6–17–05; 8:45 am]
BILLING CODE 4160–01–S
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. 2003D–0549]
Guidance for Industry on Clozapine
Tablets: In Vivo Bioequivalence and In
Vitro Dissolution Testing; Availability
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Annual Frequency per
Response
No. of Respondents
Notice.
SUMMARY: The Food and Drug
Administration (FDA) is announcing the
availability of a guidance for industry
entitled ‘‘Clozapine Tablets: In Vivo
Bioequivalence and In Vitro Dissolution
Testing.’’ The guidance was originally
published in November 1996. However,
because of potentially significant
VerDate jul<14>2003
17:24 Jun 17, 2005
Jkt 205001
adverse effects seen in healthy subjects
who had not previously used clozapine,
FDA proposed a revision to the
guidance in a draft published in
December 2003. FDA did not receive
comments on the draft guidance during
the comment period. This final version
of the 2003 draft guidance includes a
change in the recommended patient
population as well as other minor
changes that are based on current
information available to FDA.
DATES: Submit written or electronic
comments on agency guidances at any
time.
Submit written requests for
single copies of this guidance to the
Division of Drug Information (HFD–
240), Center for Drug Evaluation and
Research, Food and Drug
Administration, 5600 Fishers Lane,
Rockville, MD 20857. Send one selfaddressed adhesive label to assist that
office in processing your requests.
Submit written comments on the
guidance to the Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane, rm.
1061, Rockville, MD 20852. Submit
electronic comments to https://
www.fda.gov/dockets/ecomments. See
the SUPPLEMENTARY INFORMATION section
for electronic access to the guidance
document.
ADDRESSES:
FOR FURTHER INFORMATION CONTACT:
Lizzie Sanchez, Center for Drug
Evaluation and Research (HFD–650),
Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857,
301–827–5847.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of
a guidance for industry entitled
‘‘Clozapine Tablets: In Vivo
Bioequivalence and In Vitro Dissolution
Testing.’’ This guidance is being issued
PO 00000
Frm 00055
Fmt 4703
Sfmt 4703
because of necessary changes to
recommendations provided in a
previous guidance on the same topic
that published in November 1996. In the
Federal Register of December 30, 2003
(68 FR 75262), FDA published a
document that proposed revisions to the
1996 guidance and that provided
information to the pharmaceutical
industry regarding the design of
bioequivalence studies for generic
clozapine products.
In the 1996 guidance, FDA
recommended that doses of one-half of
a 25 milligram clozapine tablet be
administered to healthy subjects in
bioequivalence studies for generic
clozapine products. The guidance also
provided an option for conducting
studies in the appropriate patient
population. However, in the 2003 draft
guidance, FDA proposed that such
studies not be conducted in healthy
subjects because a high number of
healthy subjects experienced serious
adverse effects such as hypotension,
bradycardia, syncope, and asystole
during clozapine bioequivalence
studies. FDA did not receive comments
on the 2003 draft guidance during the
comment period.
This final version of the 2003 draft
guidance has been further revised to
provide recommendations describing
the use of an appropriate patient
population that is already stable on a
dose of clozapine. The use of healthy
subjects who had not previously used
clozapine is no longer recommended in
this final version of the guidance, which
will ensure the safety of subjects in
bioequivalence studies on clozapine.
This guidance is being issued
consistent with FDA’s good guidance
practices regulation (21 CFR 10.115).
The guidance represents the agency’s
current thinking on clozapine tablets: in
vivo and in vitro dissolution testing. It
does not create or confer any rights for
E:\FR\FM\20JNN1.SGM
20JNN1
35448
Federal Register / Vol. 70, No. 117 / Monday, June 20, 2005 / Notices
or on any person and does not operate
to bind FDA or the public. An
alternative approach may be used if
such approach satisfies the
requirements of the applicable statutes
and regulations.
II. Comments
Interested persons may submit to the
Division of Dockets Management (see
ADDRESSES) written or electronic
comments regarding this document.
Submit a single copy of electronic
comments or two paper copies of any
mailed comments, except that
individuals may submit one paper copy.
Comments are to be identified 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.
III. Electronic Access
Persons with access to the Internet
may obtain the document at either http:/
/www.fda.gov/cder/guidance/index.htm
or https://www.fda.gov/ohrms/dockets/
default.htm.
Dated: June 9, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05–12039 Filed 6–17–05; 8:45 am]
BILLING CODE 4160–01–S
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. 2005D–0223]
Draft Guidance for Industry on
Nonclinical Evaluation of Late
Radiation Toxicity of Therapeutic
Radiopharmaceuticals; Availability
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
SUMMARY: The Food and Drug
Administration (FDA) is announcing the
availability of a draft guidance for
industry entitled ‘‘Nonclinical
Evaluation of Late Radiation Toxicity of
Therapeutic Radiopharmaceuticals.’’
The purpose of this draft guidance is to
provide recommendations to industry
for designing nonclinical toxicity
studies to determine potential late
radiation toxicities (radiation-induced
injuries occurring after a latency period
of several months to years) of
therapeutic radiopharmaceuticals
administered systemically. The purpose
of such studies is to help minimize the
risk of late-occurring irreversible
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17:24 Jun 17, 2005
Jkt 205001
radiation toxicities in clinical studies of
therapeutic radiopharmaceuticals.
DATES: Submit written or electronic
comments on the draft guidance by
September 19, 2005. General comments
on agency guidance documents are
welcome at any time.
ADDRESSES: Submit written requests for
single copies of the draft guidance to the
Division of Drug Information (HFD–
240), Center for Drug Evaluation and
Research, Food and Drug
Administration, 5600 Fishers Lane,
Rockville, MD 20857. Send one selfaddressed adhesive label to assist that
office in processing your requests.
Submit written comments on the draft
guidance to the Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane, rm.
1061, Rockville, MD 20852. Submit
electronic comments to https://
www.fda.gov/dockets/ecomments. See
the SUPPLEMENTARY INFORMATION section
for electronic access to the draft
guidance document.
FOR FURTHER INFORMATION CONTACT:
Adebayo Laniyonu or Renee Tyson,
Center for Drug Evaluation and Research
(HFD–160), Food and Drug
Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301–827–7510.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of
a draft guidance for industry entitled
‘‘Nonclinical Evaluation of Late
Radiation Toxicity of Therapeutic
Radiopharmaceuticals.’’ The objective of
this guidance is to provide
recommendations to industry for
designing nonclinical toxicity studies to
determine potential late radiation
toxicities of therapeutic
radiopharmaceutical agents. This
guidance is not intended for diagnostic
radiopharmaceuticals or for
radiobiologicals (e.g., radiolabeled
monoclonal antibodies).
Late radiation toxicity differs from
early or acute radiation toxicity. Acute
radiation toxicity (e.g., bone marrow
failure, nausea, vomiting, diarrhea, and
oral mucositis) occurs within days to
weeks of an acute dose of radiation and
is often self-limiting and reversible. In
contrast, late radiation toxicity (e.g.,
renal failure, pulmonary fibrosis, and
chord transection) occurs after a latency
period of several months to years,
during which relatively normal organ
function continues. Late radiation
toxicity is usually progressive and
irreversible.
Therapeutic radiopharmaceuticals are
typically administered systemically to
treat cancer. The radiation absorbed
PO 00000
Frm 00056
Fmt 4703
Sfmt 4703
doses delivered by therapeutic
radiopharmaceuticals may be
comparable to those delivered with
external beam radiotherapy (XRT). At
therapeutic doses of radiation, the late
radiation toxicities commonly
associated with XRT (e.g., brain
necrosis, paralysis, pulmonary fibrosis,
liver or kidney failure, and hemorrhagic
cystitis) can also be seen with
therapeutic radiopharmaceuticals. With
XRT, if the total dose given to an organ
is less than its tolerance dose, the
probability of symptomatic late
radiation toxicity to that organ will be
minimal. The tolerance doses of most
human organs for conventional
fractionated XRT are known, and are
routinely used to direct the safe
administration of XRT. In FDA’s
experience, however, there are few
clinical data from which to estimate
organ tolerance doses for therapeutic
radiopharmaceuticals. Furthermore, late
radiation toxicity has been observed
when Medical Internal Radiation Dose
(MIRDOSE) estimates of radiation
absorbed doses delivered by therapeutic
radiopharmaceuticals to target organs
were substantially below the published
XRT organ tolerance doses.
Therefore, there is a need to gain
additional knowledge in this area to
support the safe administration of
therapeutic radiopharmaceuticals to
humans. Because studies in humans
would be unethical, the best means to
gain insight into this issue is by
conducting nonclinical late radiation
toxicity studies. These studies will aid
in identifying organs at risk and
establish a margin of safety for late
radiation toxicity. As a result, these
studies will help to minimize the risk of
late-occurring radiation toxicities in
clinical studies of therapeutic
radiopharmaceuticals.
This draft guidance focuses solely on
late radiation safety concerns that are
unique to therapeutic
radiopharmaceuticals, and provides
recommendations for late radiation
toxicity nonclinical study designs
including issues regarding good
laboratory practices, species selection,
dose selection, timing of study, and
study parameters.
This draft guidance is being issued
consistent with FDA’s good guidance
practices regulation (21 CFR 10.115).
The draft guidance, when finalized, will
represent the agency’s current thinking
on nonclinical evaluation of late
radiation toxicity of therapeutic
radiopharmaceuticals. It does not create
or confer any rights for or on any person
and does not operate to bind FDA or the
public. An alternative approach may be
used if such approach satisfies the
E:\FR\FM\20JNN1.SGM
20JNN1
]]>Agencies
[Federal Register Volume 70, Number 117 (Monday, June 20, 2005)]
[Notices]
[Pages 35447-35448]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-12039]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2003D-0549]
Guidance for Industry on Clozapine Tablets: In Vivo
Bioequivalence and In Vitro Dissolution Testing; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a guidance for industry entitled ``Clozapine Tablets:
In Vivo Bioequivalence and In Vitro Dissolution Testing.'' The guidance
was originally published in November 1996. However, because of
potentially significant adverse effects seen in healthy subjects who
had not previously used clozapine, FDA proposed a revision to the
guidance in a draft published in December 2003. FDA did not receive
comments on the draft guidance during the comment period. This final
version of the 2003 draft guidance includes a change in the recommended
patient population as well as other minor changes that are based on
current information available to FDA.
DATES: Submit written or electronic comments on agency guidances at any
time.
ADDRESSES: Submit written requests for single copies of this guidance
to the Division of Drug Information (HFD-240), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857. Send one self-addressed adhesive label to
assist that office in processing your requests. Submit written comments
on the guidance to the Division of Dockets Management (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. Submit electronic comments to https://www.fda.gov/dockets/
ecomments. See the SUPPLEMENTARY INFORMATION section for electronic
access to the guidance document.
FOR FURTHER INFORMATION CONTACT: Lizzie Sanchez, Center for Drug
Evaluation and Research (HFD-650), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-5847.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a guidance for industry
entitled ``Clozapine Tablets: In Vivo Bioequivalence and In Vitro
Dissolution Testing.'' This guidance is being issued because of
necessary changes to recommendations provided in a previous guidance on
the same topic that published in November 1996. In the Federal Register
of December 30, 2003 (68 FR 75262), FDA published a document that
proposed revisions to the 1996 guidance and that provided information
to the pharmaceutical industry regarding the design of bioequivalence
studies for generic clozapine products.
In the 1996 guidance, FDA recommended that doses of one-half of a
25 milligram clozapine tablet be administered to healthy subjects in
bioequivalence studies for generic clozapine products. The guidance
also provided an option for conducting studies in the appropriate
patient population. However, in the 2003 draft guidance, FDA proposed
that such studies not be conducted in healthy subjects because a high
number of healthy subjects experienced serious adverse effects such as
hypotension, bradycardia, syncope, and asystole during clozapine
bioequivalence studies. FDA did not receive comments on the 2003 draft
guidance during the comment period.
This final version of the 2003 draft guidance has been further
revised to provide recommendations describing the use of an appropriate
patient population that is already stable on a dose of clozapine. The
use of healthy subjects who had not previously used clozapine is no
longer recommended in this final version of the guidance, which will
ensure the safety of subjects in bioequivalence studies on clozapine.
This guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents the
agency's current thinking on clozapine tablets: in vivo and in vitro
dissolution testing. It does not create or confer any rights for
[[Page 35448]]
or on any person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
requirements of the applicable statutes and regulations.
II. Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified 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.
III. Electronic Access
Persons with access to the Internet may obtain the document at
either https://www.fda.gov/cder/guidance/index.htm or https://
www.fda.gov/ohrms/dockets/default.htm.
Dated: June 9, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-12039 Filed 6-17-05; 8:45 am]
BILLING CODE 4160-01-S
