Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Current Good Manufacturing Practices and Related Regulations for Blood and Blood Components; and Requirements for Donor Testing, Donor Notification, and “Lookback”, 61447-61451 [05-21153]
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Federal Register / Vol. 70, No. 204 / Monday, October 24, 2005 / Notices
submission of meeting requests and
information packages under the
guidance.
statements about the product and a
description of the purpose and details of
the meeting.
C. Request For a Formal Meeting
D. Information Package
Based on data collected from the
review divisions and offices within
CDER and CBER, FDA estimates that
approximately 713 sponsors and
applicants (respondents) request
approximately 1,783 formal meetings
with CDER annually and approximately
164 respondents request approximately
286 formal meetings with CBER
annually regarding the development and
review of a PDUFA product. The hours
per response, which is the estimated
number of hours that a respondent
would spend preparing the information
to be submitted with a meeting request
in accordance with the guidance, is
estimated to be approximately 10 hours.
Based on FDA’s experience, the agency
expects it will take respondents this
amount of time to gather and copy brief
Based on data collected from the
review divisions and offices within
CDER and CBER, FDA estimates that
approximately 615 respondents
submitted approximately 1,365
information packages to CDER annually
and approximately 132 respondents
submitted approximately 208
information packages to CBER annually
prior to a formal meeting regarding the
development and review of a PDUFA
product. The hours per response, which
is the estimated number of hours that a
respondent would spend preparing the
information package in accordance with
the guidance, is estimated to be
approximately 18 hours. Based on
FDA’s experience, the agency expects it
will take respondents this amount of
time to gather and copy brief statements
61447
about the product, a description of the
details for the anticipated meeting, and
data and information that generally
would already have been compiled for
submission to the agency.
As stated earlier, the guidance
provides information on how the agency
will interpret and apply section 119(a)
of the Modernization Act, specific
PDUFA goals for the management of
meetings associated with the review of
human drug applications for PDUFA
products, and provisions of existing
regulations describing certain meetings
(§§ 312.47 and 312.82). The information
collection provisions in § 312.47
concerning End of Phase 2 meetings and
Pre NDA meetings have been approved
by OMB (OMB control number 0910–
0014). However, the guidance provides
additional recommendations for
submitting information to FDA in
support of a meeting request. As a
result, FDA is submitting for OMB
approval these additional estimates.
TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN
Meeting Requests and Information
Packages
Number of Respondents
Number of Responses
Per Respondent
Total Annual Responses
Hours Per Response
Total Hours
Meeting Requests
CDER
713
2.50
1,783
10
17,830
CBER
164
1.74
286
10
2,860
Total
20,690
Information Packages
CDER
615
2.22
1,365
18
24,570
CBER
132
1.58
208
18
3,744
Total
28,314
Grand Total
49,004
Dated: October 17, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05–21151 Filed 10–21–05; 8:45 am]
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
BILLING CODE 4160–01–S
[Docket No. 2005N–0220]
Agency Information Collection
Activities; Submission for Office of
Management and Budget Review;
Comment Request; Current Good
Manufacturing Practices and Related
Regulations for Blood and Blood
Components; and Requirements for
Donor Testing, Donor Notification, and
‘‘Lookback’’
AGENCY:
Food and Drug Administration,
HHS.
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ACTION:
Notice.
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.
DATES: Fax written comments on the
collection of information by November
23, 2005.
ADDRESSES: OMB is still experiencing
significant delays in the regular mail,
including first class and express mail,
and messenger deliveries are not being
accepted. To ensure that comments on
the information collection are received,
OMB recommends that written
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Federal Register / Vol. 70, No. 204 / Monday, October 24, 2005 / Notices
comments be faxed to the Office of
Information and Regulatory Affairs,
OMB, Attn: Fumie Yokota, Desk Officer
for FDA, FAX: 202–395–6974.
FOR FURTHER INFORMATION CONTACT:
Jonna Capezzuto, Office of Management
Programs (HFA–250), Food and Drug
Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301–827–4659.
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.
Current Good Manufacturing Practices
and Related Regulations for Blood and
Blood Components; and Requirements
for Donor Testing, Donor Notification,
and ‘‘Lookback’’ (OMB Control Number
0910–0116)—Extension
Under the statutory requirements
contained in section 351 of the Public
Health Service Act (PHS Act) (42 U.S.C.
262), no blood, blood component, or
derivative may move in interstate
commerce unless: (1) It is propagated or
manufactured and prepared at an
establishment holding an unsuspended
and unrevoked license; (2) the product
complies with regulatory standards
designed to ensure safety, purity, and
potency; and (3) it bears a label plainly
marked with the product’s proper name,
manufacturer, and expiration date. In
addition, under the biologics licensing
and quarantine provisions in sections
351–361 of the PHS Act (42 U.S.C. 262–
264) and the general administrative
provisions under sections 501–503,
505–510, and 701–704 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C.
351–353, 355–360, and 371–374), FDA
has the authority to issue and enforce
regulations designed to protect the
public from unsafe or ineffective
biological products and to issue
regulations necessary to prevent the
introduction, transmission, or spread of
communicable diseases between States
or possession or from foreign countries
into the States or possession. The
current good manufacturing practice
(CGMP) and related regulations
implement FDA’s statutory authority to
ensure the safety, purity, and potency of
blood and blood components. The
‘‘lookback’’ requirements are intended
to help ensure the continued safety of
the blood supply by providing necessary
information to users of blood and blood
components and appropriate
notification of recipients of transfusion
who are at increased risk for
transmitting human immunodeficiency
virus (HIV) infection. The public health
objective in testing human blood donors
for evidence of infection due to
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communicable disease agents and in
donor notification is to prevent the
transmission of communicable disease.
The information collection
requirements in the CGMP, donor
testing, donor notification, and
‘‘lookback’’ regulations provide FDA
with the necessary information to
perform its duty to ensure the safety,
purity, and potency of blood and blood
components. These requirements
establish accountability and traceability
in the processing and handling of blood
and blood components and enables FDA
to conduct meaningful inspections. The
recordkeeping requirements serve
preventative and remedial purposes.
The disclosure requirements identify
the various blood and blood
components and important properties of
the product, demonstrate that the CGMP
requirements have been met, and
facilitate the tracing of a product back
to its original source. The reporting
requirements inform FDA of any
deviations that occur and that may
require immediate corrective action.
Under the reporting requirements,
§ 606.170(b) (21 CFR 606.170(b))
requires that fatal complications of
blood collection and transfusions be
reported to FDA as soon as possible and
that a written report shall be submitted
within 7 days. Section 610.40(c)(1)(ii)
(21 CFR 610.40(c)(1)(ii)) requires each
dedicated donation be labeled as
required under 21 CFR 606.121 and
with a label entitled ‘‘INTENDED
RECIPIENT INFORMATION LABEL’’
containing the name and identifying
information of the recipient. Section
610.40(g)(2) requires an establishment to
obtain written approval from FDA to
ship human blood or blood components
for further manufacturing use prior to
completion of testing. Section
610.40(h)(2)(ii)(A) requires an
establishment to obtain written approval
from FDA to use or ship human blood
or blood components found to be
reactive by a screening test for evidence
of a communicable disease agent(s) or
collect from a donor with a record of a
reactive screening test. Sections
610.40(h)(2)(ii)(C) and (h)(2)(ii)(D)
require an establishment to label
reactive human blood and blood
components with the appropriate
screening test results, and, if they are
intended for further manufacturing use
into injectable products, with a
statement indicating the exempted use
specifically approved by FDA. Section
610.40(h)(2)(vi) requires each donation
of human blood or blood component
that tests reactive by a screening test for
syphilis and is determined to be a
biological false positive be labeled with
both test results. Section 610.42(a) (21
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CFR 610.42(a)) requires a warning
statement, including the identity of the
communicable disease agent, on
medical devices containing human
blood or blood components found to be
reactive by a screening test for evidence
of infection due to a communicable
disease agent(s) or syphilis. Section
610.46(a) (21 CFR 610.46(a)) requires
blood establishments to notify
consignees, within 72 hours, of
repeatedly reactive test results so that
previously collected blood and blood
components are appropriately
quarantined. Section 610.46(b) requires
blood establishments to notify
consignees of licensed, more specific
test results for HIV within 30 calendar
days after the donors’ repeatedly
reactive test. Section 610.47(b) (21 CFR
610.47(b)) requires transfusion services
not subject to the Centers for Medicare
and Medicaid Services (CMS)
regulations to notify physicians of prior
donation recipients or to notify
recipients themselves of the need for
HIV testing and counseling. Section
630.6(a) (21 CFR 630.6(a)) requires an
establishment to make reasonable
attempts to notify any donor who has
been deferred as required by § 610.41
(21 CFR 610.41), or who has been
determined not to be eligible as a donor.
Section 630.6(d)(1) requires an
establishment to provide certain
information to the referring physician of
an autologous donor who is deferred
based on the results of tests as described
in § 610.41.
Under the recordkeeping
requirements, § 606.100(b) (21 CFR
606.100(b)) requires that written
standard operating procedures (SOPs)
be maintained for the collection,
processing, compatibility testing,
storage, and distribution of blood and
blood components used for transfusion
and manufacturing purposes. Section
606.100(c) requires the review of all
pertinent records to a lot or unit of
blood prior to release. Any unexplained
discrepancy or failure of a lot or unit of
final product to meet any of its
specifications must be thoroughly
investigated, and the investigation,
including conclusions and followup,
must be recorded. Section 606.110(a)
(21 CFR 606.110(a)) requires a physician
to certify in writing that the donor’s
health permits plateletpheresis or
leukapheresis if a variance from
additional regulatory standards for a
specific product is used when obtaining
the product from a specific donor for a
specific recipient. Section 606.110(b)
requires establishments to request prior
Center for Biologics Evaluation and
Research (CBER) approval for
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plasmapheresis of donors who do not
meet donor requirements. The
information collection requirements for
§ 606.110(b) are reported and approved
under OMB control number 0910–0338
which expires August 31, 2005. Section
606.151(e) (21 CFR 606.151(e)) requires
that records of expedited transfusions in
life-threatening emergencies be
maintained. So that all steps in the
collection, processing, compatibility
testing, storage and distribution, quality
control, and transfusion reaction reports
and complaints for each unit of blood
and blood components can be clearly
traced, § 606.160 (21 CFR 606.160)
requires that legible and indelible
contemporaneous records of each
significant step be made and maintained
for no less than 5 years. Section
606.160(b)(1)(ix) requires a facility to
maintain records of notification of
donors deferred or determined not to be
eligible for donation, including
appropriate followup if the initial
notification attempt fails. Section
606.160(b)(1)(xi) requires an
establishment to maintain records of
notification of the referring physician of
a deferred autologous donor, including
appropriate followup if the initial
notification attempt fails. Section
606.165 (21 CFR 606.165) requires that
distribution and receipt records be
maintained to facilitate recalls, if
necessary. Section 606.170(a) requires
records to be maintained of any reports
of complaints of adverse reactions as a
result of blood collection or transfusion.
Each such report must be thoroughly
investigated, and a written report,
including conclusions and followup,
must be prepared and maintained.
Section 610.40(g)(1) requires an
establishment to appropriately
document a medical emergency for the
release of human blood or blood
components prior to completion of
required testing.
In addition to the CGMPs in part 606
(21 CFR part 606), there are regulations
in part 640 (21 CFR part 640) that
require additional standards for certain
blood and blood components as follows:
Sections 640.3(a)(1), (a)(2), and (f);
640.4(a)(1) and (a)(2); 640.25(b)(4) and
(c)(1); 640.27(b); 640.31(b); 640.33(b);
640.51(b); 640.53(b) and (c); 640.56(b)
and (d); 640.61; 640.63(b)(3), (e)(1), and
(e)(3); 640.65(b)(2); 640.66; 640.71(b)(1);
640.72; 640.73; and 640.76(a) and (b).
The information collection requirements
and estimated burdens for these
regulations are included in the part 606
burden estimates, as described in Tables
1 and 2 of this document.
Respondents to this collection of
information are licensed and unlicensed
blood establishments that collect blood
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and blood components, including
Source Plasma and Source Leukocytes
inspected by FDA, and other transfusion
services inspected by CMS. Based on
information received from CBER’s
database systems, there are
approximately 81 licensed Source
Plasma collection establishments with
multiple locations and 1,628 registered
Whole Blood collection establishments
for a total of 1,709 establishments. There
are approximately 2,156 registered
blood establishments inspected by FDA.
Of these establishments, approximately
773 perform plateletpheresis and
leukopheresis. These establishments
annually collect approximately 28
million units of Whole Blood, blood
components including Source Plasma,
and Source Leukocytes and are required
to follow FDA ‘‘lookback’’ procedures,
and approximately 134 are registered
transfusion services that are not subject
to CMS’s ‘‘lookback’’ regulations. Based
on CMS records, there are an estimated
4,980 transfusion services approved for
Medicare reimbursement.
The following reporting and
recordkeeping estimates are based on
information provided by industry, CMS,
and FDA experience. Based on
information received from industry, we
estimate that there are an average of 13
million donations of Source Plasma
from approximately 2 million donors
and 15 million donations of Whole
Blood, including 300,000 (2 percent of
15 million) autologous, from
approximately 8 million donors.
Assuming each autologous donor makes
an average of 2 donations, FDA
estimates that there are approximately
150,000 autologous donors.
FDA estimates that approximately 5
percent (12,000) of the 240,000
donations that are donated specifically
for the use of an identified recipient
would be tested under the dedicated
donors testing provisions in
§ 610.40(c)(1)(ii).
Under § 610.40(g)(2) and (h)(2)(ii)(A),
the only product currently shipped
prior to completion of testing is a
licensed product, Source Leukocytes,
used in the manufacture of interferon,
which requires rapid preparation from
blood. Shipments of Source Leukocytes
are preapproved under a biologics
license application and each shipment
does not have to be reported to the
agency. Based on information from
CBER’s database system, FDA receives
an estimated 1 application per year from
manufacturers of Source Leukocytes.
Under § 610.40(h)(2)(ii)(C) and
(h)(2)(ii)(D), FDA estimates that each
manufacturer would ship an estimated 1
human blood or blood component per
month (12 per year) that would require
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61449
two labels; one as reactive for the
appropriate screening test under
§ 610.40(h)(2)(ii)(C), and the other
stating the exempted use specifically
approved by FDA under
§ 610.40(h)(2)(ii)(D). According to
CBER’s database system, there are an
estimated 40 licensed manufacturers
that ship known reactive human blood
or blood components.
Based on information we received
from industry, we estimate that
approximately 18,000 donations
annually test reactive by a screening test
for syphilis, and are determined to be
biological false positives by additional
testing and labeled accordingly
(§ 610.40(h)(2)(vi)).
Human blood or a blood component
with a reactive screening test, as a
component of a medical device, is an
integral part of the medical device, e.g.,
a positive control for an in vitro
diagnostic testing kit. It is usual and
customary business practice for
manufacturers to include on the
container label a warning statement that
identifies the communicable disease
agent. In addition, on the rare occasion
when a human blood or blood
component with a reactive screening
test is the only component available for
a medical device that does not require
a reactive component, then a statement
of warning is required to be affixed to
the medical device. To account for this
rare occasion under § 610.42(a), we
estimate that the warning statement
would be necessary no more than once
a year.
Based on information received from
industry, we estimate that there are
approximately 4,424 repeat donors that
will test reactive on a screening test for
HIV with 159 confirmed positive. We
estimate that each repeat donor has
donated two previous times and an
average of three components were made
from each donation. Under § 610.46(a)
and (b), this estimate results in 26,544
(4,424 x 2 x 3) notifications of the HIV
screening test results to consignees by
collecting establishments for the
purpose of quarantining affected blood
and blood components, and another
26,544 (4,424 x 2 x 3) notifications to
consignees of subsequent test results.
Under § 610.47(b), based also on the
information received from industry, we
estimate that 80 percent of the 159 (127)
confirmed HIV positive were from
repeat donors of Whole Blood
donations.
Industry estimates that approximately
13 percent of 10 million potential
donors (1.3 million donors) who come
to donate annually are determined not
to be eligible for donation prior to
collection because of failure to satisfy
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eligibility criteria. It is the usual and
customary business practice of 1,709
collecting establishments to notify
onsite and to explain the reason why the
donor is determined not to be suitable
for donating. Based on such available
information, we estimate that two-thirds
of the 1,709 collecting establishments
provided onsite additional information
and counseling to a donor determined
not to be eligible for donation as usual
and customary business practice.
Consequently, we estimate that only
one-third or 570 collection
establishments would need to provide,
under § 630.6(a), additional information
and counseling onsite to the estimated
433,333 (one-third of 1.3 million)
ineligible donors.
It is estimated that another 4.5 percent
of 10 million donors (450,000 donors)
are deferred annually based on test
results. We estimate that currently 95
percent of the establishments that
collect 98 percent of the blood and
blood components notify donors who
have reactive test results for HIV,
Hepatitis B Virus (HBV), Hepatitis C
Virus (HCV), Human T-Lymphotropic
Virus (HTLV), and syphilis as usual and
customary business practice.
Consequently, 5 percent (85) of the
industry (1,709) collecting 2 percent
(9,000) of the deferred donors (450,000)
would notify donor under § 630.6(a).
establishments collect autologous
donations and, therefore, are required to
notify referring physicians. We estimate
that 4.5 percent of the 150,000
autologous donors (6,750) will be
deferred under § 610.41 and thus result
in the notification of their referring
physicians.
FDA has concluded that the use of
untested or incompletely tested but
appropriately documented human blood
or blood components in rare medical
emergencies should not be prohibited.
We estimate the recordkeeping under
§ 610.40(g)(1) to be minimal with one or
less occurrence per year. The reporting
of test results to the consignee in
§ 610.40(g) does not create a new burden
for respondents because it is the usual
and customary business practice or
procedure to finish the testing and
provide the results to the manufacturer
responsible for labeling the blood
products.
The hours per response and hours per
record are based on estimates received
from industry or FDA experience with
similar recordkeeping or reporting
requirements.
In the Federal Register of June 21,
2005 (70 FR 35680), FDA published a
60-day notice requesting public
comment on the information collection
provisions. No comments were received.
FDA estimates the burden of this
collection of information as follows:
As part of usual and customary
business practice, collecting
establishments notify an autologous
donor’s referring physician of reactive
test results obtained during the donation
process required under § 630.6(d)(1).
However, we estimate that 5 percent of
the 1,628 blood collection
establishments (81) may not notify the
referring physicians of the estimated 2
percent of 150,000 autologous donors
with reactive test results (3,000) as their
usual and customary business practice.
The recordkeeping chart reflects the
estimate that 95 percent of the
recordkeepers, which collect 98 percent
of the blood supply, had developed
SOPs as part of their customary and
usual business practice. Establishments
may minimize burdens associated with
CGMP and related regulations by using
model SOPs developed by industries’
accreditation organizations. These
accreditation organizations represent
almost all registered blood
establishments.
Under § 606.160(b)(1)(ix), we estimate
the total annual records based on the 1.3
million donors determined not to be
eligible to donate and each of the
450,000 (1,300,000 + 450,000 =
1,750,000) donors deferred based on
reactive test results for evidence of
infection due to communicable disease
agents. Under § 606.160(b)(1)(xi), only
the 1,628 registered blood
TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1
21 CFR Section
No. of
Respondents
606.170(b)2
Annual Frequency
per Response
Total Annual
Responses
Hours per
Response
Total Hours
82
1
82
1,628
8
12,000
610.40(g)(2)
1
1
1
1
1
610.40(h)(2)(ii)(A)
1
1
1
1
1
40
12
480
1,628
11
18,000
610.42(a)
1
1
1
610.46(a)
1,709
16
26,544
0.17
4,512
610.46(b)
1,709
16
26,544
0.17
4,512
610.47(b)
134
1
134
630.6(a)3
570
760
433,333
630.6(a)4
85
106
630.6(d)(1)
81
37
610.40(c)(1)(ii)
610.40(h)(2)(ii)(C) and
(h)(2)(ii)(D)
610.40(h)(2)(vi)
20
0.08
960
0.2
0.08
96
1,440
1
1
1
134
0.08
34,667
9,000
1.5
13,500
3,000
1
Total
3,000
64,464
1There
2The
1,640
are no capital costs or operating and maintenance costs associated with this collection of information.
reporting requirement in § 640.73, which addresses the reporting of fatal donor reactions, is included in the estimate for § 606.170(b).
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3Notification
4Notification
61451
of donors determined not to be eligible for donation based on failure to satisfy eligibility criteria.
of donors deferred based on reactive test results for evidence of infection due to communicable disease agents.
TABLE 2.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1
No. of
Recordkeepers
21 CFR Section
Annual Frequency
per Recordkeeping
Total Annual
Records
Hours per
Record
Total Hours
606.100(b)2
2495
1
249
24
5,976
606.100(c)
2495
10
2,490
1
2,490
606.110(a)3
396
1
39
606.151(e)
2495
12
2,988
606.1604
2495
1,928
480,000
0.75
360,000
606.160(b)(1)(ix)
1,709
1,024
1,750,000
0.05
87,500
606.160(b)(1)(xi)
1,628
4
6,750
0.05
338
606.165
2495
1,928
480,000
606.170(a)
2495
12
2,988
1
610.40(g)(1)
1,628
1
1,628
0.5
0.5
0.083
0.083
Total
20
248
39,840
2,988
814
500,214
1There
are no capital costs or operating and maintenance costs associated with this collection of information.
recordkeeping requirements in §§ 640.3(a)(1), 640.4(a)(1), and 640.66, which address the maintenance of SOPs, are included in the estimate for § 606.100(b).
3The recordkeeping requirements in § 640.27(b), which address the maintenance of donor health records for the plateletpheresis, are included
in the estimate for § 606.110(a).
4The recordkeeping requirements in §§ 640.3(a)(2) and (f); 640.4(a)(2); 640.25(b)(4) and (c)(1); 640.31(b); 640.33(b); 640.51(b); 640.53(b) and
(c); 640.56(b) and (d); 640.61; 640.63(b)(3), (e)(1), and (e)(3); 640.65(b)(2); 640.71(b)(1); 640.72; and 640.76(a) and (b), which address the
maintenance of various records are included in the estimate for § 606.160.
5Five percent of CMS transfusion services and FDA-registered blood establishments (0.05 X 4,980).
6Five percent of plateletpheresis and leukopheresis establishments (0.05 X 773).
2The
Dated: October 17, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05–21153 Filed 10–21–05; 8:45 am]
BILLING CODE 4160–01–S
the Paperwork Reduction Act of 1995
(the PRA).
Fax written comments on the
collection of information by November
23, 2005.
DATES:
OMB is still experiencing
significant delays in the regular mail,
including first class and express mail,
and messenger deliveries are not being
accepted. 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: Fumie Yokota, Desk Officer
for FDA, FAX: 202–395–6974.
ADDRESSES:
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. 2004D–0283]
Agency Information Collection
Activities; Submission for Office of
Management and Budget Review;
Comment Request; Waivers of In Vivo
Demonstration of Bioequivalence of
Animal Drugs in Soluble Powder Oral
Dosage Form Products and Type A
Medicated Articles
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
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
15:19 Oct 21, 2005
Denver Presley, Office of Management
Programs (HFA–250), Food and Drug
Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301–827–1472.
In
compliance with 44 U.S.C. 3507, FDA
has submitted the following proposed
collection of information to OMB for
review and clearance.
SUPPLEMENTARY INFORMATION:
Notice.
VerDate Aug<31>2005
FOR FURTHER INFORMATION CONTACT:
Jkt 208001
PO 00000
Frm 00029
Fmt 4703
Sfmt 4703
Waivers of In Vivo Demonstration of
Bioequivalence of Animal Drugs in
Soluble Powder Oral Dosage Form
Products and Type A Medicated
Articles
The generic Animal Drug and Patent
Term Registration Act of 1988 permitted
generic drug manufacturers to copy
those pioneer drug products that were
no longer subject to patent or other
marketing exclusivity protection. The
approval for marketing these generic
products is based in part upon a
demonstration of bioequivalence
between the generic product and
pioneer product. This guidance clarifies
circumstances under which FDA
believes the demonstration of
bioequivalence by the stature does not
need to be established on the basis of in
vivo studies for soluble powder oral
dosage form products and Type A
medicated articles. The data submitted
in support of the waiver request are
necessary to validate the waiver
decision.
The requirement to establish
bioequivalence through in vivo studies
(blood level bioequivalence or clinical
endpoint bioequivalence) may be
waived for soluble powder or Type A
medicated articles in either of two
E:\FR\FM\24OCN1.SGM
24OCN1
]]>Agencies
[Federal Register Volume 70, Number 204 (Monday, October 24, 2005)]
[Notices]
[Pages 61447-61451]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-21153]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2005N-0220]
Agency Information Collection Activities; Submission for Office
of Management and Budget Review; Comment Request; Current Good
Manufacturing Practices and Related Regulations for Blood and Blood
Components; and Requirements for Donor Testing, Donor Notification, and
``Lookback''
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
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.
DATES: Fax written comments on the collection of information by
November 23, 2005.
ADDRESSES: OMB is still experiencing significant delays in the regular
mail, including first class and express mail, and messenger deliveries
are not being accepted. To ensure that comments on the information
collection are received, OMB recommends that written
[[Page 61448]]
comments be faxed to the Office of Information and Regulatory Affairs,
OMB, Attn: Fumie Yokota, Desk Officer for FDA, FAX: 202-395-6974.
FOR FURTHER INFORMATION CONTACT: Jonna Capezzuto, Office of Management
Programs (HFA-250), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-4659.
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.
Current Good Manufacturing Practices and Related Regulations for Blood
and Blood Components; and Requirements for Donor Testing, Donor
Notification, and ``Lookback'' (OMB Control Number 0910-0116)--
Extension
Under the statutory requirements contained in section 351 of the
Public Health Service Act (PHS Act) (42 U.S.C. 262), no blood, blood
component, or derivative may move in interstate commerce unless: (1) It
is propagated or manufactured and prepared at an establishment holding
an unsuspended and unrevoked license; (2) the product complies with
regulatory standards designed to ensure safety, purity, and potency;
and (3) it bears a label plainly marked with the product's proper name,
manufacturer, and expiration date. In addition, under the biologics
licensing and quarantine provisions in sections 351-361 of the PHS Act
(42 U.S.C. 262-264) and the general administrative provisions under
sections 501-503, 505-510, and 701-704 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 351-353, 355-360, and 371-374), FDA has the
authority to issue and enforce regulations designed to protect the
public from unsafe or ineffective biological products and to issue
regulations necessary to prevent the introduction, transmission, or
spread of communicable diseases between States or possession or from
foreign countries into the States or possession. The current good
manufacturing practice (CGMP) and related regulations implement FDA's
statutory authority to ensure the safety, purity, and potency of blood
and blood components. The ``lookback'' requirements are intended to
help ensure the continued safety of the blood supply by providing
necessary information to users of blood and blood components and
appropriate notification of recipients of transfusion who are at
increased risk for transmitting human immunodeficiency virus (HIV)
infection. The public health objective in testing human blood donors
for evidence of infection due to communicable disease agents and in
donor notification is to prevent the transmission of communicable
disease.
The information collection requirements in the CGMP, donor testing,
donor notification, and ``lookback'' regulations provide FDA with the
necessary information to perform its duty to ensure the safety, purity,
and potency of blood and blood components. These requirements establish
accountability and traceability in the processing and handling of blood
and blood components and enables FDA to conduct meaningful inspections.
The recordkeeping requirements serve preventative and remedial
purposes. The disclosure requirements identify the various blood and
blood components and important properties of the product, demonstrate
that the CGMP requirements have been met, and facilitate the tracing of
a product back to its original source. The reporting requirements
inform FDA of any deviations that occur and that may require immediate
corrective action.
Under the reporting requirements, Sec. 606.170(b) (21 CFR
606.170(b)) requires that fatal complications of blood collection and
transfusions be reported to FDA as soon as possible and that a written
report shall be submitted within 7 days. Section 610.40(c)(1)(ii) (21
CFR 610.40(c)(1)(ii)) requires each dedicated donation be labeled as
required under 21 CFR 606.121 and with a label entitled ``INTENDED
RECIPIENT INFORMATION LABEL'' containing the name and identifying
information of the recipient. Section 610.40(g)(2) requires an
establishment to obtain written approval from FDA to ship human blood
or blood components for further manufacturing use prior to completion
of testing. Section 610.40(h)(2)(ii)(A) requires an establishment to
obtain written approval from FDA to use or ship human blood or blood
components found to be reactive by a screening test for evidence of a
communicable disease agent(s) or collect from a donor with a record of
a reactive screening test. Sections 610.40(h)(2)(ii)(C) and
(h)(2)(ii)(D) require an establishment to label reactive human blood
and blood components with the appropriate screening test results, and,
if they are intended for further manufacturing use into injectable
products, with a statement indicating the exempted use specifically
approved by FDA. Section 610.40(h)(2)(vi) requires each donation of
human blood or blood component that tests reactive by a screening test
for syphilis and is determined to be a biological false positive be
labeled with both test results. Section 610.42(a) (21 CFR 610.42(a))
requires a warning statement, including the identity of the
communicable disease agent, on medical devices containing human blood
or blood components found to be reactive by a screening test for
evidence of infection due to a communicable disease agent(s) or
syphilis. Section 610.46(a) (21 CFR 610.46(a)) requires blood
establishments to notify consignees, within 72 hours, of repeatedly
reactive test results so that previously collected blood and blood
components are appropriately quarantined. Section 610.46(b) requires
blood establishments to notify consignees of licensed, more specific
test results for HIV within 30 calendar days after the donors'
repeatedly reactive test. Section 610.47(b) (21 CFR 610.47(b)) requires
transfusion services not subject to the Centers for Medicare and
Medicaid Services (CMS) regulations to notify physicians of prior
donation recipients or to notify recipients themselves of the need for
HIV testing and counseling. Section 630.6(a) (21 CFR 630.6(a)) requires
an establishment to make reasonable attempts to notify any donor who
has been deferred as required by Sec. 610.41 (21 CFR 610.41), or who
has been determined not to be eligible as a donor. Section 630.6(d)(1)
requires an establishment to provide certain information to the
referring physician of an autologous donor who is deferred based on the
results of tests as described in Sec. 610.41.
Under the recordkeeping requirements, Sec. 606.100(b) (21 CFR
606.100(b)) requires that written standard operating procedures (SOPs)
be maintained for the collection, processing, compatibility testing,
storage, and distribution of blood and blood components used for
transfusion and manufacturing purposes. Section 606.100(c) requires the
review of all pertinent records to a lot or unit of blood prior to
release. Any unexplained discrepancy or failure of a lot or unit of
final product to meet any of its specifications must be thoroughly
investigated, and the investigation, including conclusions and
followup, must be recorded. Section 606.110(a) (21 CFR 606.110(a))
requires a physician to certify in writing that the donor's health
permits plateletpheresis or leukapheresis if a variance from additional
regulatory standards for a specific product is used when obtaining the
product from a specific donor for a specific recipient. Section
606.110(b) requires establishments to request prior Center for
Biologics Evaluation and Research (CBER) approval for
[[Page 61449]]
plasmapheresis of donors who do not meet donor requirements. The
information collection requirements for Sec. 606.110(b) are reported
and approved under OMB control number 0910-0338 which expires August
31, 2005. Section 606.151(e) (21 CFR 606.151(e)) requires that records
of expedited transfusions in life-threatening emergencies be
maintained. So that all steps in the collection, processing,
compatibility testing, storage and distribution, quality control, and
transfusion reaction reports and complaints for each unit of blood and
blood components can be clearly traced, Sec. 606.160 (21 CFR 606.160)
requires that legible and indelible contemporaneous records of each
significant step be made and maintained for no less than 5 years.
Section 606.160(b)(1)(ix) requires a facility to maintain records of
notification of donors deferred or determined not to be eligible for
donation, including appropriate followup if the initial notification
attempt fails. Section 606.160(b)(1)(xi) requires an establishment to
maintain records of notification of the referring physician of a
deferred autologous donor, including appropriate followup if the
initial notification attempt fails. Section 606.165 (21 CFR 606.165)
requires that distribution and receipt records be maintained to
facilitate recalls, if necessary. Section 606.170(a) requires records
to be maintained of any reports of complaints of adverse reactions as a
result of blood collection or transfusion. Each such report must be
thoroughly investigated, and a written report, including conclusions
and followup, must be prepared and maintained. Section 610.40(g)(1)
requires an establishment to appropriately document a medical emergency
for the release of human blood or blood components prior to completion
of required testing.
In addition to the CGMPs in part 606 (21 CFR part 606), there are
regulations in part 640 (21 CFR part 640) that require additional
standards for certain blood and blood components as follows: Sections
640.3(a)(1), (a)(2), and (f); 640.4(a)(1) and (a)(2); 640.25(b)(4) and
(c)(1); 640.27(b); 640.31(b); 640.33(b); 640.51(b); 640.53(b) and (c);
640.56(b) and (d); 640.61; 640.63(b)(3), (e)(1), and (e)(3);
640.65(b)(2); 640.66; 640.71(b)(1); 640.72; 640.73; and 640.76(a) and
(b). The information collection requirements and estimated burdens for
these regulations are included in the part 606 burden estimates, as
described in Tables 1 and 2 of this document.
Respondents to this collection of information are licensed and
unlicensed blood establishments that collect blood and blood
components, including Source Plasma and Source Leukocytes inspected by
FDA, and other transfusion services inspected by CMS. Based on
information received from CBER's database systems, there are
approximately 81 licensed Source Plasma collection establishments with
multiple locations and 1,628 registered Whole Blood collection
establishments for a total of 1,709 establishments. There are
approximately 2,156 registered blood establishments inspected by FDA.
Of these establishments, approximately 773 perform plateletpheresis and
leukopheresis. These establishments annually collect approximately 28
million units of Whole Blood, blood components including Source Plasma,
and Source Leukocytes and are required to follow FDA ``lookback''
procedures, and approximately 134 are registered transfusion services
that are not subject to CMS's ``lookback'' regulations. Based on CMS
records, there are an estimated 4,980 transfusion services approved for
Medicare reimbursement.
The following reporting and recordkeeping estimates are based on
information provided by industry, CMS, and FDA experience. Based on
information received from industry, we estimate that there are an
average of 13 million donations of Source Plasma from approximately 2
million donors and 15 million donations of Whole Blood, including
300,000 (2 percent of 15 million) autologous, from approximately 8
million donors. Assuming each autologous donor makes an average of 2
donations, FDA estimates that there are approximately 150,000
autologous donors.
FDA estimates that approximately 5 percent (12,000) of the 240,000
donations that are donated specifically for the use of an identified
recipient would be tested under the dedicated donors testing provisions
in Sec. 610.40(c)(1)(ii).
Under Sec. 610.40(g)(2) and (h)(2)(ii)(A), the only product
currently shipped prior to completion of testing is a licensed product,
Source Leukocytes, used in the manufacture of interferon, which
requires rapid preparation from blood. Shipments of Source Leukocytes
are preapproved under a biologics license application and each shipment
does not have to be reported to the agency. Based on information from
CBER's database system, FDA receives an estimated 1 application per
year from manufacturers of Source Leukocytes.
Under Sec. 610.40(h)(2)(ii)(C) and (h)(2)(ii)(D), FDA estimates
that each manufacturer would ship an estimated 1 human blood or blood
component per month (12 per year) that would require two labels; one as
reactive for the appropriate screening test under Sec.
610.40(h)(2)(ii)(C), and the other stating the exempted use
specifically approved by FDA under Sec. 610.40(h)(2)(ii)(D). According
to CBER's database system, there are an estimated 40 licensed
manufacturers that ship known reactive human blood or blood components.
Based on information we received from industry, we estimate that
approximately 18,000 donations annually test reactive by a screening
test for syphilis, and are determined to be biological false positives
by additional testing and labeled accordingly (Sec. 610.40(h)(2)(vi)).
Human blood or a blood component with a reactive screening test, as
a component of a medical device, is an integral part of the medical
device, e.g., a positive control for an in vitro diagnostic testing
kit. It is usual and customary business practice for manufacturers to
include on the container label a warning statement that identifies the
communicable disease agent. In addition, on the rare occasion when a
human blood or blood component with a reactive screening test is the
only component available for a medical device that does not require a
reactive component, then a statement of warning is required to be
affixed to the medical device. To account for this rare occasion under
Sec. 610.42(a), we estimate that the warning statement would be
necessary no more than once a year.
Based on information received from industry, we estimate that there
are approximately 4,424 repeat donors that will test reactive on a
screening test for HIV with 159 confirmed positive. We estimate that
each repeat donor has donated two previous times and an average of
three components were made from each donation. Under Sec. 610.46(a)
and (b), this estimate results in 26,544 (4,424 x 2 x 3) notifications
of the HIV screening test results to consignees by collecting
establishments for the purpose of quarantining affected blood and blood
components, and another 26,544 (4,424 x 2 x 3) notifications to
consignees of subsequent test results.
Under Sec. 610.47(b), based also on the information received from
industry, we estimate that 80 percent of the 159 (127) confirmed HIV
positive were from repeat donors of Whole Blood donations.
Industry estimates that approximately 13 percent of 10 million
potential donors (1.3 million donors) who come to donate annually are
determined not to be eligible for donation prior to collection because
of failure to satisfy
[[Page 61450]]
eligibility criteria. It is the usual and customary business practice
of 1,709 collecting establishments to notify onsite and to explain the
reason why the donor is determined not to be suitable for donating.
Based on such available information, we estimate that two-thirds of the
1,709 collecting establishments provided onsite additional information
and counseling to a donor determined not to be eligible for donation as
usual and customary business practice. Consequently, we estimate that
only one-third or 570 collection establishments would need to provide,
under Sec. 630.6(a), additional information and counseling onsite to
the estimated 433,333 (one-third of 1.3 million) ineligible donors.
It is estimated that another 4.5 percent of 10 million donors
(450,000 donors) are deferred annually based on test results. We
estimate that currently 95 percent of the establishments that collect
98 percent of the blood and blood components notify donors who have
reactive test results for HIV, Hepatitis B Virus (HBV), Hepatitis C
Virus (HCV), Human T-Lymphotropic Virus (HTLV), and syphilis as usual
and customary business practice. Consequently, 5 percent (85) of the
industry (1,709) collecting 2 percent (9,000) of the deferred donors
(450,000) would notify donor under Sec. 630.6(a).
As part of usual and customary business practice, collecting
establishments notify an autologous donor's referring physician of
reactive test results obtained during the donation process required
under Sec. 630.6(d)(1). However, we estimate that 5 percent of the
1,628 blood collection establishments (81) may not notify the referring
physicians of the estimated 2 percent of 150,000 autologous donors with
reactive test results (3,000) as their usual and customary business
practice.
The recordkeeping chart reflects the estimate that 95 percent of
the recordkeepers, which collect 98 percent of the blood supply, had
developed SOPs as part of their customary and usual business practice.
Establishments may minimize burdens associated with CGMP and related
regulations by using model SOPs developed by industries' accreditation
organizations. These accreditation organizations represent almost all
registered blood establishments.
Under Sec. 606.160(b)(1)(ix), we estimate the total annual records
based on the 1.3 million donors determined not to be eligible to donate
and each of the 450,000 (1,300,000 + 450,000 = 1,750,000) donors
deferred based on reactive test results for evidence of infection due
to communicable disease agents. Under Sec. 606.160(b)(1)(xi), only the
1,628 registered blood establishments collect autologous donations and,
therefore, are required to notify referring physicians. We estimate
that 4.5 percent of the 150,000 autologous donors (6,750) will be
deferred under Sec. 610.41 and thus result in the notification of
their referring physicians.
FDA has concluded that the use of untested or incompletely tested
but appropriately documented human blood or blood components in rare
medical emergencies should not be prohibited. We estimate the
recordkeeping under Sec. 610.40(g)(1) to be minimal with one or less
occurrence per year. The reporting of test results to the consignee in
Sec. 610.40(g) does not create a new burden for respondents because it
is the usual and customary business practice or procedure to finish the
testing and provide the results to the manufacturer responsible for
labeling the blood products.
The hours per response and hours per record are based on estimates
received from industry or FDA experience with similar recordkeeping or
reporting requirements.
In the Federal Register of June 21, 2005 (70 FR 35680), FDA
published a 60-day notice requesting public comment on the information
collection provisions. No comments were received.
FDA estimates the burden of this collection of information as
follows:
TABLE 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual Hours per
21 CFR Section Respondents per Response Responses Response Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.170(b)\2\ 82 1 82 20 1,640
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.40(c)(1)(ii) 1,628 8 12,000 0.08 960
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.40(g)(2) 1 1 1 1 1
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.40(h)(2)(ii)(A) 1 1 1 1 1
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.40(h)(2)(ii)(C) and (h)(2)(ii)(D) 40 12 480 0.2 96
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.40(h)(2)(vi) 1,628 11 18,000 0.08 1,440
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.42(a) 1 1 1 1 1
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.46(a) 1,709 16 26,544 0.17 4,512
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.46(b) 1,709 16 26,544 0.17 4,512
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.47(b) 134 1 134 1 134
--------------------------------------------------------------------------------------------------------------------------------------------------------
630.6(a)\3\ 570 760 433,333 0.08 34,667
--------------------------------------------------------------------------------------------------------------------------------------------------------
630.6(a)\4\ 85 106 9,000 1.5 13,500
--------------------------------------------------------------------------------------------------------------------------------------------------------
630.6(d)(1) 81 37 3,000 1 3,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total 64,464
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\The reporting requirement in Sec. 640.73, which addresses the reporting of fatal donor reactions, is included in the estimate for Sec.
606.170(b).
[[Page 61451]]
\3\Notification of donors determined not to be eligible for donation based on failure to satisfy eligibility criteria.
\4\Notification of donors deferred based on reactive test results for evidence of infection due to communicable disease agents.
TABLE 2.--Estimated Annual Recordkeeping Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
No. of Annual Frequency Total Annual
21 CFR Section Recordkeepers per Recordkeeping Records Hours per Record Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.100(b)\2\ 249\5\ 1 249 24 5,976
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.100(c) 249\5\ 10 2,490 1 2,490
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.110(a)\3\ 39\6\ 1 39 0.5 20
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.151(e) 249\5\ 12 2,988 0.083 248
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.160\4\ 249\5\ 1,928 480,000 0.75 360,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.160(b)(1)(ix) 1,709 1,024 1,750,000 0.05 87,500
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.160(b)(1)(xi) 1,628 4 6,750 0.05 338
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.165 249\5\ 1,928 480,000 0.083 39,840
--------------------------------------------------------------------------------------------------------------------------------------------------------
606.170(a) 249\5\ 12 2,988 1 2,988
--------------------------------------------------------------------------------------------------------------------------------------------------------
610.40(g)(1) 1,628 1 1,628 0.5 814
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total 500,214
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\The recordkeeping requirements in Sec. Sec. 640.3(a)(1), 640.4(a)(1), and 640.66, which address the maintenance of SOPs, are included in the
estimate for Sec. 606.100(b).
\3\The recordkeeping requirements in Sec. 640.27(b), which address the maintenance of donor health records for the plateletpheresis, are included in
the estimate for Sec. 606.110(a).
\4\The recordkeeping requirements in Sec. Sec. 640.3(a)(2) and (f); 640.4(a)(2); 640.25(b)(4) and (c)(1); 640.31(b); 640.33(b); 640.51(b); 640.53(b)
and (c); 640.56(b) and (d); 640.61; 640.63(b)(3), (e)(1), and (e)(3); 640.65(b)(2); 640.71(b)(1); 640.72; and 640.76(a) and (b), which address the
maintenance of various records are included in the estimate for Sec. 606.160.
\5\Five percent of CMS transfusion services and FDA-registered blood establishments (0.05 X 4,980).
\6\Five percent of plateletpheresis and leukopheresis establishments (0.05 X 773).
Dated: October 17, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-21153 Filed 10-21-05; 8:45 am]
BILLING CODE 4160-01-S
