[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

[[Page 10472]]

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

[[Page 10473]]

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