[Federal Register Volume 64, Number 42 (Thursday, March 4, 1999)]
[Notices]
[Pages 10470-10474]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-5387]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 98N-0222]
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 reinstatement 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 uses for marketed drugs, biologics, and devices.
DATES: Submit written comments on the collection of information by May
3, 1999.
ADDRESSES: Submit written comments on the collection of information to
the Dockets Management Branch (HFA-305), Food and Drug Administration,
[[Page 10471]]
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 Information
Resources Management (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 reinstatement 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: (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
Description: In the Federal Register of November 20, 1998 (63 FR
64555), FDA published a final rule to add 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 (FDAMA) (Pub. L. 105-115). In brief,
section 401 of FDAMA amended the act 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 legally marketed; 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 have 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 and 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 rule sets forth the criteria and procedures for making such
submissions to FDA. Under the rule, a submission would include a
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 would include 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 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 rule prescribes the timeframe within which the manufacturer shall
maintain records that would enable it to take corrective action. The
rule requires the manufacturer to submit lists pertaining to the
disseminated articles and reference publications and the categories of
persons (or individuals) receiving the information and to submit 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 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 would
receive and the number of manufacturers who would be subject to part 99
on the number of efficacy and new use supplements for approved drugs,
biologics, and devices received in fiscal year (FY) 1997 and on a
projected increase in supplements due to FDAMA. In FY 1997, FDA
received 198 efficacy and new use supplements from 115 manufacturers.
The number of supplements increased 100 percent from FY 1995 to FY 1997
as a result of two new initiatives, the Prescription Drug User Fee Act
and a new pediatric labeling regulation. If FDAMA results in an
additional 50 percent increase in the number of supplements and a
corresponding increase in the number of manufacturers, then the
estimated number of submissions under part 99 is 297 (198 + (0.5 x
198)), and the estimated number of manufacturers is 172 (115 + (0.5 x
115)). These figures are reflected in Tables 1 and 2 of this document
for Secs. 99.201(a)(1), 99.201(a)(2), 99.201(a)(3), 99.201(b),
99.201(c), 99.501(a)(1), 99.501(a)(2), 99.501(b)(1), 99.501(b)(3), and
99.501(c).
The estimated burden hours for these provisions follow.
Section 99.201(a)(1) requires the manufacturer to provide an
identical copy of the information to be disseminated, including any
required information. Because the manufacturer must compile this
information in order to prepare its submission to FDA, FDA estimates
that 40 hours would be required per submission. Because 297 annual
responses are expected under Sec. 99.201(a)(1), the total burden for
this provision is 11,880 hours (297 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
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assembling, reviewing, and submitting the information and assumes that
the manufacturer will have already acquired some of this information in
order to decide whether to disseminate information on an unapproved use
under part 99. The total burden for this provision is 7,128 hours (297
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 would be required for the explanation because the
manufacturer would have developed and used its search strategy before
preparing the bibliography. Because 297 annual responses are expected
under Sec. 99.201(a)(3), the total burden for this provision is 297
hours (297 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 297 annual
responses are expected under Sec. 99.201(b), the total burden for this
provision is 148.5 hours (297 response x 0.5 hours per response = 148.5
hours).
Section 99.201(c) requires the manufacturer to provide two copies
with its original submission. FDA does not expect that copying the
submission will be time-consuming and estimates the burden to be 30
minutes. Because 297 annual responses are expected under
Sec. 99.201(c), the total burden for this provision is 148.5 hours.
Yet, while FDAMA requires manufacturers to provide a submission to
FDA before they disseminate information on unapproved/new uses, it also
permits manufacturers to: (1) Have completed studies and promise to
submit a supplemental application for the new use within 6 months after
the date of initial dissemination; (2) provide protocols and a schedule
for completing studies and submitting a supplemental application for
the new use within 36 months after the date of initial dissemination;
(3) have completed studies and have submitted a supplemental
application for the new use; or (4) request an exemption from the
requirement to submit a supplemental application. These possible
scenarios are addressed in Secs. 99.201(a)(4)(i)(A),
99.201(a)(4)(ii)(A), 99.201(a)(5), and 99.205(b) respectively.
To determine the number of responses in Secs. 99.201(a)(4)(i)(A),
99.201(a)(4)(ii)(A), 99.201(a)(5), and 99.205(b), FDA began by
estimating the number of requests for an exemption under
Sec. 99.205(b). The legislative history indicates that such exemptions
are to be limited. In the final rule, FDA estimated that approximately
10 percent of all respondents would seek--or 10 percent of all
submissions would contain--an ``economically prohibitive'' exemption
(resulting in 17 total respondents and approximately 30 annual
responses) and that the estimated reporting burden per response would
be 82 hours. This results in a total hour burden of 2,460 hours for
Sec. 99.205(b) (30 submissions x 82 hours per submission).
The estimated increase in the number of exemption requests results
in a corresponding decrease in the remaining number of respondents and
submissions under Secs. 99.201(a)(4)(i)(A), 99.201(a)(4)(ii)(A), and
99.201(a)(5). FDA assumes that the remaining 267 submissions (297 total
submissions--30 submissions containing an exemption request) will be
divided equally among Secs. 99.201(a)(4)(i)(A), 99.201(a)(4)(ii)(A),
and 99.201(a)(5), resulting in 89 responses in each provision (267
submissions/3 provisions). FDA has estimated the number of respondents
in a similar fashion ((172 total respondents--17 respondents submitting
an exemption request)/3 provisions = 51.6, rounded up to 52 respondents
per provision).
As stated earlier, Sec. 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) must be
submitted with the application. FDA estimates that 30 hours would be
required for this response because this is information that each
manufacturer already maintains for its drugs or devices. The total
burden for this provision is 2,670 hours (89 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 would 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 total burden for this
provision is 5,340 hours (89 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 would be
needed because manufacturers already maintain this information. The
total burden for this provision is 89 hours (89 annual responses x 1
hour per response).
Under Sec. 99.203, a manufacturer who 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 1 annual response), and that such requests
will result in a reporting burden of 10 hours per request. The 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
study cannot be completed on time, and an estimate of the additional
time needed. FDA estimates that 10 hours for reporting the required
information under Sec. 99.203(b) because it would require consultation
between the manufacturer and key individuals (such as the study's
principal investigator(s)). As in the case of Sec. 99.203(a), the
expected number of responses is very small (1 annual response), and the
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
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554(c)(3) of the Federal Food, Drug, and Cosmetic Act (the act) (21
U.S.C. 360aaa-3(c)(3))), and FDA estimates that these copies would
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 total number of annual responses is 2, resulting in a total
burden hour for this provision of 1 hour (2 annual responses x 0.5
hours per response).
The remaining reporting and recordkeeping burdens follow.
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 whether it needs to
maintain records identifying individual recipients due to special
safety considerations associated with the new use. This means that, in
most cases, the manufacturer will only have to maintain records
identifying recipients by category. In either event, the manufacturer
will know whether 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 297 annual responses are expected under Sec. 99.501(a)(1),
the total burden for this provision is 2,970 hours (297 annual
responses x 10 hours per response).
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 297
annual responses are expected under Sec. 99.501(a)(2), the total burden
for this provision is 297 hours (297 annual responses x 1 hour per
response).
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 tentatively
estimates a burden of 8 hours for this provision. The actual 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 total burden for this provision is 4,752 hours (297
responses submitted semiannually x 8 hours per response = 297 x 2 x 8 =
4,752 hours).
Section 553(a)(2) of the act (21 U.S.C. 360aaa-2(a)(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 297 submissions under part 99 results in disseminated information,
Sec. 99.501(b)(2) would result in 594 lists (297 submissions x 2
submissions/year) 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 total burden for this provision is 594 hours (594 lists x 1
hour per list).
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 a total burden of 11,880 hours for this
provision (297 annual responses submitted semiannually x 20 hours per
response = 297 x 2 x 20 = 11,880 hours).
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. Based on FDA's regulatory experience in monitoring
studies to support supplemental applications, FDA estimates this would
affect only 1 percent of all applications (297 x 0.01 = 2.97, rounded
up to 3) and only 2 manufacturers (172 x 0.01 = 1.72, rounded up to 2).
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 total burden hours for this provision is 6
hours (3 annual responses 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 cannot determine, at this time, how many
exemption requests will be granted, but, for purposes of this
information of collection, has estimated that 10 percent of all
submissions will contain an exemption request (297 total submissions x
0.10 = 29.7, rounded up to 30) and has assumed that all exemption
requests will be granted, for a total of 30 annual responses. 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 tentatively
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 a total
burden of 1,230 hours for this provision (30 annual responses 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 hour for this provision to be 1 hour. Because 297
annual responses are expected under Sec. 99.501(c), the total burden
for this provision is 297 hours.
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 Burden1
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Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
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99.201(a)(1) 172 1.7 297 40 11,880
99.201(a)(2) 172 1.7 297 24 7,128
99.201(a)(3) 172 1.7 297 1 297
99.201(a)(4)(i)(A) 52 1.7 89 30 2,670
99.201(a)(4)(ii)(A) 52 1.7 89 60 5,340
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99.201(a)(5) 52 1.7 89 1 89
99.201(b) 172 1.7 297 0.5 148.5
99.201(c) 172 1.7 297 0.5 148.5
99.203(a) 1 1 1 10 10
99.203(b) 1 1 1 10 10
99.203(c) 2 1 2 0.5 1
99.205(b) 17 1.8 30 82 2,460
99.501(b)(1) 172 3.4 594 8 4,752
99.501(b)(2) 172 3.4 594 1 594
99.501(b)(3) 172 3.4 594 20 11,880
99.501(b)(4) 2 1.7 3 2 6
99.501(b)(5) 17 1.8 30 41 1,230
Total Hours 48,644
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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 Burden1
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Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Recordkeepers Recordkeeping Records Recordkeeper
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99.501(a)(1) 172 1.7 297 10 2,970
99.501(a)(2) 172 1.7 297 1 297
99.501(c) 172 1.7 297 1 297
Total Hours 3,564
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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 this rule is 52,208 hours.
Dated: February 26, 1999.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 99-5387 Filed 3-3-99; 8:45 am]
BILLING CODE 4160-01-F