[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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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