[Federal Register: June 16, 2005 (Volume 70, Number 115)]
[Notices]
[Page 35099-35103]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr16jn05-52]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2005N-0208]
Agency Information Collection Activities; Proposed Collection;
Comment Request; Dissemination of Information on Unapproved/New Uses
for Marketed Drugs, Biologics, and Devices
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing an
opportunity for public comment on the proposed collection of certain
information by the agency. Under the Paperwork Reduction Act of 1995
(the PRA), Federal agencies are required to publish notice in the
Federal Register concerning each proposed collection of information,
including each proposed extension of an existing collection of
information, and to allow 60 days for public comment in response to the
notice. This notice solicits comments on the reporting and
recordkeeping requirements associated with the dissemination of
unapproved or new
[[Page 35100]]
uses for marketed drugs, biologics, and devices.
DATES: Submit written or electronic comments on the collection of
information by August 15, 2005.
ADDRESSES: Submit electronic comments on the collection of information
to: http://www.fda.gov/dockets/ecomments. Submit written comments on
the collection of information to the Division of Dockets Management
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. All comments should be identified with the docket
number found in brackets in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Management
Programs (HFA-250), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-827-1482.
SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal
agencies must obtain approval from the Office of Management and Budget
(OMB) for each collection of information they conduct or sponsor.
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes agency requests or requirements that members of
the public submit reports, keep records, or provide information to a
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A))
requires Federal agencies to provide a 60-day notice in the Federal
Register concerning each proposed collection of information, including
each proposed extension of an existing collection of information,
before submitting the collection to OMB for approval. To comply with
this requirement, FDA is publishing notice of the proposed collection
of information set forth in this document.
With respect to the following collection of information, FDA
invites comments on these topics: (1) Whether the proposed collection
of information is necessary for the proper performance of FDA's
functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
Dissemination of Information on Unapproved/New Uses for Marketed Drugs,
Biologics, and Devices (OMB Control Number 0910-0390)--Extension
In the Federal Register of November 20, 1998 (63 FR 64556), FDA
published a final rule that added a new part 99 (21 CFR part 99)
entitled ``Dissemination of Information on Unapproved/New Uses for
Marketed Drugs, Biologics, and Devices.''
The final rule implemented section 401 of the Food and Drug
Administration Modernization Act of 1997 (FDAMA) (Public Law 105-115).
In brief, section 401 of FDAMA amended the Federal Food, Drug, and
Cosmetic Act (the act) (21 U.S.C. 360aaa through 360aaa-6) to permit
drug, biologic, and device manufacturers to disseminate certain written
information concerning the safety, effectiveness, or benefits of a use
that is not described in the product's approved labeling to health care
practitioners, pharmacy benefit managers, health insurance issuers,
group health plans, and Federal and State Government agencies, provided
that the manufacturer complies with certain statutory requirements. For
example, the information that is to be disseminated must be about a
drug or device that is being marketed legally; it must be in the form
of an unabridged reprint or copy of a peer-reviewed journal article or
reference publication; and it must not be derived from another
manufacturer's clinical research, unless that other manufacturer has
given its permission for the dissemination. The information must be
accompanied by certain information, including a prominently displayed
statement that the information discusses a use (or uses) that has not
been approved or cleared by FDA. Additionally, 60 days before
dissemination, the manufacturer must submit to FDA a copy of the
information to be disseminated, any other clinical trial information
that the manufacturer has relating to the safety or effectiveness of
the new use, any reports of clinical experience that pertain to the
safety of the new use, and a summary of such information.
The final rule sets forth the criteria and procedures for making
such submissions to FDA. Under the final rule, submissions include
certification that the manufacturer has completed clinical studies
necessary to submit a supplemental application to FDA for the new use,
and will submit the supplemental application within 6 months after its
initial dissemination of information. If the manufacturer has planned,
but not completed, such studies, the submission includes proposed
protocols and a schedule for conducting the studies, as well as a
certification that the manufacturer will complete the clinical studies
and submit a supplemental application no later than 36 months after its
initial dissemination of information. The final rule also permits
manufacturers to request extensions of the time period for completing a
study and submitting a supplemental application, and to request an
exemption from the requirement to submit a supplemental application.
The final rule prescribes the timeframe within which the manufacturer
shall maintain records that would enable it to take corrective action.
The final rule requires the manufacturer to submit lists pertaining to
the disseminated articles and reference publications, the categories of
persons (or individuals) receiving the information, and a notice and
summary of any additional research or data (and a copy of the data)
relating to the product's safety or effectiveness for the new use. The
final rule requires the manufacturer to maintain a copy of the
information, lists, records, and reports for 3 years after it has
ceased dissemination of the information and to make the documents
available to FDA for inspection and copying.
FDA based its estimates of the number of submissions it will
receive, and the number of manufacturers who would be subject to part
99, on the average of the total number of required submissions received
during 2002, 2003, and 2004. The estimated burden hours for these
provisions are based on the following calculations:
Section 99.201(a)(1) requires the manufacturer to provide an
identical copy of the information to be disseminated, including any
information required under Sec. 99.103. Because the manufacturer must
compile this information in order to prepare its submission to FDA, FDA
estimates that 40 hours will be required per submission. Because 10
annual responses are expected under Sec. 99.201(a)(1), the estimated
total burden for this provision is 400 hours (10 annual responses x 40
hours per response).
Section 99.201(a)(2) requires the manufacturer to submit clinical
trial information pertaining to the safety and effectiveness of the new
use, clinical experience reports on the safety of the new use, and a
summary of the information. FDA estimates 24 burden hours per response
for this provision for assembling, reviewing, and submitting the
information and assumes that the manufacturer will have already
acquired
[[Page 35101]]
some of this information in order to decide whether to disseminate
information on an unapproved use under part 99. The estimated total
burden for this provision is 240 hours (10 annual responses x 24 hours
per response).
Section 99.201(a)(3) requires the manufacturer to explain its
search strategy when assembling its bibliography. FDA estimates that
only 1 hour will be required for the explanation because the
manufacturer would have developed and used its search strategy before
preparing the bibliography. Because 10 annual responses are expected
under Sec. 99.201(a)(3), the estimated total burden for this provision
is 10 hours (10 annual responses x 1 hour per response).
Section 99.201(b) simply requires the manufacturer's attorney,
agent, or other authorized official to sign its submissions,
certifications, and requests for an exemption. FDA estimates that only
30 minutes are necessary for such signatures. Because 10 annual
responses are expected under Sec. 99.201(b), the estimated total
burden for this provision is 5 hours (10 annual responses x 0.5 hours
per response).
Section 99.201(c) requires the manufacturer to provide two copies
with its original submission. Copying the submission should not be
time-consuming, so FDA estimates the burden to be 30 minutes. Because
10 annual responses are expected under Sec. 99.201(c), the estimated
total burden for this provision is 5 hours (10 annual responses x 0.5
hours per response).
While the act requires manufacturers to provide a submission to FDA
before they disseminate information on unapproved/new uses, it also
permits the following actions for manufacturers: (1) To have completed
studies and promise to submit a supplemental application for the new
use within 6 months after the date of initial dissemination; (2) to
provide protocols, a schedule for completing studies, and submit a
supplemental application for the new use within 36 months after the
date of initial dissemination; (3) to have completed studies and have
submitted a supplemental application for the new use; or (4) to request
an exemption from the requirement to submit a supplemental application.
These possible scenarios are addressed in Sec. Sec.
99.201(a)(4)(i)(A), (a)(4)(ii)(A), (a)(5), and 99.205(b). Based on the
average of the total number of required submissions received during
2002, 2003, and 2004, FDA has made the following burden estimates:
Section 99.201(a)(4)(i)(A) requires the manufacturer, if the
manufacturer has completed studies needed for the submission of a
supplemental application for the new use, to submit the protocol(s) for
the completed studies, or, if the protocol was submitted to an
investigational new drug application (IND) or investigational device
exemption (IDE), to submit the IND or IDE number(s), the date of
submission of the protocol(s), the protocol number(s), and the date of
any amendments to the protocol(s). FDA estimates that 30 hours will be
required for this response because this is information that each
manufacturer already maintains for its drugs or devices. The estimated
total burden for this provision is 210 hours (7 annual responses x 30
hours per response).
For manufacturers who submit protocols and a schedule for
conducting studies, Sec. 99.201(a)(4)(ii)(A) requires the manufacturer
to include, in its schedule, the projected dates on which the
manufacturer expects the principal study events to occur. FDA estimates
a manufacturer will need approximately 60 hours to include the
projected dates because it would have to contact the studies' principal
investigator(s) and other company officials. The estimated total burden
for this provision is 420 hours (7 annual responses x 60 hours per
response).
If the manufacturer has submitted a supplemental application for
the new use, Sec. 99.201(a)(5) requires a cross-reference to that
supplemental application. FDA estimates that only 1 hour will be needed
because manufacturers already maintain this information. The estimated
total burden for this provision is 2 hours (2 annual responses x 1 hour
per response).
FDA has not received any requests for an exemption under Sec.
99.205(b). However, for purposes of this request for OMB approval, FDA
estimates that annually one manufacturer may submit one exemption
request under Sec. 99.205(b). FDA estimates that the reporting burden
for each exemption request will be 82 hours. The estimated total burden
for this provision is 82 hours (1 annual response x 82 hours per
response).
Under Sec. 99.203, a manufacturer that has certified that it will
complete studies necessary to submit a supplemental application within
36 months after its submission to FDA, but later finds that it will be
unable to complete such studies or submit a supplemental application
within that time period, may request an extension of time from FDA.
Such requests for extension should be limited, occurring less than 1
percent of the time, because manufacturers and FDA, when developing or
reviewing study protocols, should be able to identify when a study will
require more than 36 months to complete. Section 99.203 contemplates
extension requests under two different scenarios. Under Sec.
99.203(a), a manufacturer may make an extension request before it makes
a submission to FDA regarding the dissemination of information under
part 99. The agency expects such requests to be limited, occurring less
than 1 percent of the time (or one annual response), and that such
requests will result in a reporting burden of 10 hours per request. The
estimated total burden hours for this provision, therefore, is 10 hours
(1 annual response x 10 hours per response). Section 99.203(b)
specifies the contents of a request to extend the time for completing
planned studies after the manufacturer has provided its submission to
FDA. The required information includes a description of the studies,
the current status of the studies, reasons why the studies cannot be
completed on time, and an estimate of the additional time needed. FDA
estimates that 10 hours will be needed for reporting the required
information under Sec. 99.203(b) because it would require consultation
between the manufacturer and key individuals (such as the studies'
principal investigator(s)). As in the case of Sec. 99.203(a), the
expected number of responses is very small (one annual response), and
the estimated total burden hours for this provision is 10 hours (1
annual response x 10 hours per response).
Section 99.203(c) requires two copies of an extension request (in
addition to the request required under section 554(c)(3) of the act (21
U.S.C. 360aaa-3)). FDA estimates that these copies will result in a
minimal reporting burden of 30 minutes. However, this requirement would
apply to extension requests under Sec. 99.203(a) and (b), so the
estimated total number of annual responses is two, resulting in an
estimated total burden for this provision of 1 hour (2 annual responses
x 0.5 hours per response).
The remaining reporting and recordkeeping burdens are shown in the
following estimates:
Section 99.501(a)(1) requires the manufacturer to maintain records
that identify recipients by category or individually. Under Sec.
99.301(a)(3), FDA will notify the manufacturer if it needs to maintain
records identifying individual recipients because of special safety
considerations associated with the new use. This means that, in most
cases, the manufacturer will only have
[[Page 35102]]
to maintain records identifying recipients by category. In either
event, the manufacturer will know if it must maintain records that
identify individual recipients before it begins disseminating
information. The time required to identify recipients individually
should be minimal, and the time required to identify recipients by
category should be even less. Therefore, FDA estimates the burden for
this provision to be 10 hours, and, because 8 annual records are
expected under Sec. 99.501(a)(1), the estimated total burden for this
provision is 80 hours (8 annual records x 10 hours per record).
Section 99.501(a)(2) requires the manufacturer to maintain a copy
of the information it disseminates. This task is not expected to be
time-consuming, so FDA estimates the burden to be 1 hour. Because 8
annual records are expected under Sec. 99.501(a)(2), the estimated
total burden for this provision is 8 hours (8 annual records x 1 hour
per record).
Section 99.501(b)(1) requires the manufacturer to submit to FDA
semiannually a list containing the articles and reference publications
that were disseminated in the preceding 6-month period. FDA estimates a
burden of 8 hours for this provision. The burden may be less if the
manufacturer develops and updates the list while it disseminates
articles and reference publications during the 6-month period (as
opposed to generating a completely new list at the end of each 6-month
period), and if the volume of disseminated materials is small. The
estimated total burden for this provision is 160 hours (10 responses
submitted semiannually x 8 hours per response).
Section 99.501(b)(2) requires manufacturers that disseminate
information to submit to FDA semiannually a list that identifies the
categories of providers who received the articles and reference
publications. Section 99.501(b)(2) also requires the list to identify
which category of recipients received each particular article or
reference publication. If each of the 10 submissions under part 99
results in disseminated information, Sec. 99.501(b)(2) would result in
20 lists (10 submissions x 2 submissions semiannually) identifying
which category of recipients received each particular article or
reference publication. The agency estimates the burden to be only 1
hour per response because this type of information is maintained as a
usual and customary business practice, and the estimated total burden
for this provision is 20 hours (20 responses submitted semiannually x 1
hour per response).
In relation to Sec. 99.201(a)(2), Sec. 99.501(b)(3) requires the
manufacturer to provide, on a semiannual basis, a notice and summary of
any additional clinical research or other data relating to the safety
and effectiveness of the new use and, if it possesses such research or
data, to provide a copy to FDA. This burden should not be as extensive
as that in Sec. 99.201(a)(2), so FDA estimates the burden to be 20
hours per response, for an estimated total burden of 400 hours for this
provision (10 responses submitted semiannually x 20 hours per
response).
If a manufacturer discontinues or terminates a study before
completing it, Sec. 99.501(b)(4) requires the manufacturer to state
the reasons for discontinuing or terminating the study in its next
progress report. FDA estimates that annually this will affect only 1
percent of all applications (8 x 0.01 = 0.08, rounded up to 1) and only
one manufacturer. FDA estimates 2 hours of reporting time for this
requirement because the manufacturer should know the reasons for
discontinuing or terminating the study and would only need to provide
those reasons in its progress report. The estimated total burden hours
for this provision is 2 hours (1 annual response x 2 hours per
response).
Section 99.501(b)(5) requires the manufacturer to submit any new or
additional information that relates to whether the manufacturer
continues to meet the requirements for the exemption after an exemption
has been granted. FDA estimates that 10 percent of all submissions will
contain an exemption request (8 annual submissions x 0.10 = 0.8,
rounded up to 1), and has assumed that all exemption requests will be
granted, for a total of 1 annual response. The information sought under
Sec. 99.501(b)(5) pertains solely to new or additional information and
is not expected to be as extensive as the information required to
obtain an exemption. Thus, FDA estimates the burden for Sec.
99.501(b)(5) to be 41 hours per response (or half the burden associated
with an exemption request), for an estimated total burden of 41 hours
for this provision (1 annual response x 41 hours per response).
Section 99.501(c) requires the manufacturer to maintain records for
3 years after it has ceased dissemination of the information. FDA
estimates the burden for this provision to be 1 hour. Because eight
annual records are expected under Sec. 99.501(c), the estimated total
burden for this provision is 8 hours (8 annual records x 1 hour per
record).
The estimates for Sec. Sec. 99.201(a)(1), (a)(2), (a)(3), (b), and
(c), and 99.501(b)(1), (b)(2), and (b)(3) have been increased by two
responses each to account for manufacturer resubmissions. In addition,
the estimate for Sec. 99.201(a)(4)(i)(A) and (a)(4)(ii)(A) has been
increased by one response each to account for manufacturer
resubmissions.
Description of Respondents: All manufacturers (persons and
businesses, including small businesses) of drugs, biologics, and device
products.
FDA estimates the burden of this collection of information as
follows:
Table 1.--Estimated Annual Reporting Burden \1\
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No. of Annual responses Total annual Hours per
21 CFR section respondents per respondent responses response Total hours
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99.201(a)(1) 5 1 10 40 400
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99.201(a)(2) 5 1 10 24 240
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99.201(a)(3) 5 1 10 1 10
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99.201(a)(4)(i)(A) 6 1 7 30 210
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99.201(a)(4)(ii)(A) 6 1 7 60 420
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99.201(a)(5) 1 1 2 1 2
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[[Page 35103]]
99.201(b) 5 1 10 0.5 5
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99.201(c) 5 1 10 0.5 5
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99.203(a) 1 1 1 10 10
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99.203(b) 1 1 1 10 10
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99.203(c) 1 1 2 0.5 1
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99.205(b) 1 1 1 82 82
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99.501(b)(1) 5 3 20 8 160
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99.501(b)(2) 5 1 20 1 20
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99.501(b)(3) 5 1 20 20 400
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99.501(b)(4) 1 1 1 2 2
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99.501(b)(5) 1 1 1 41 41
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Total Hours 2,018
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 2.--Estimated Annual Recordkeeping Burden\1\
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No. of Annual Frequency per Total Annual
21 CFR Section Recordkeepers Recordkeeping Records Hours per Record Total Hours
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99.501(a)(1) 5 1 8 10 80
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99.501(a)(2) 5 1 8 1 8
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99.501(c) 5 1 8 1 8
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Total Hours 96
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
The estimated burden associated with the information collection
requirements for these regulations is 2,114 hours.
Dated: June 9, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-11863 Filed 6-15-05; 8:45 am]
BILLING CODE 4160-01-S