[Federal Register Volume 64, Number 141 (Friday, July 23, 1999)]
[Notices]
[Pages 40008-40012]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-18767]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 98N-0222]


Agency Information Collection Activities; Submission for OMB 
Review; 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 that the 
proposed collection of information listed below has been submitted to 
the Office of Management and Budget (OMB) for review and clearance 
under the Paperwork Reduction Act of 1995 (the PRA).

DATES: Submit written comments on the collection of information by 
August 23, 1999.
ADDRESSES: Submit written comments on the collection of information to 
the

[[Page 40009]]

Office of Information and Regulatory Affairs, OMB, New Executive Office 
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Wendy 
Taylor, Desk Officer for FDA.

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: In compliance with section 3507 of the PRA 
(44 U.S.C. 3507), FDA has submitted the following proposed collection 
of information to OMB for review and clearance.

Dissemination of Information on Unapproved/New Uses for Marketed 
Drugs, Biologics, and Devices (OMB Control No. 0910-0390)--
Extension

    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 Federal Food, 
Drug, and Cosmetic Act (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 are provided in the 
following paragraphs of this document.
    Section 99.201(a)(1) requires the manufacturer to provide an 
identical copy of the information to be disseminated, including any 
required information. The manufacturer must compile this information 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 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. The manufacturer 
would have developed and used its search strategy before preparing the 
bibliography. FDA estimates that 1 hour would be required for the 
explanation. 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) requires the manufacturer's attorney, agent, or 
other authorized official to sign its submissions, certifications, and 
requests for an exemption. FDA estimates that 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

[[Page 40010]]

will be time-consuming. FDA 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.
    While the act 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. This is information that each 
manufacturer already maintains for its drugs or devices. FDA estimates 
that 30 hours would be required for this response. 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. Manufacturers 
would have to contact the studies' principal investigator(s) and other 
company officials. FDA estimates a manufacturer would need 
approximately 60 hours to include the projected dates. 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. Manufacturers already maintain this 
information. FDA estimates that 1 hour would be needed to comply with 
the requirement. 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 554(c)(3) of the act (21 
U.S.C. 360aaa-3)). FDA estimates that these copies would result in a 
reporting burden of 30 minutes. 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).
    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. 
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).

[[Page 40011]]

    Section 99.501(a)(2) requires the manufacturer to maintain a copy 
of the information it disseminates. 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) 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 per 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). 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 at 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.
    In the Federal Register of March 4, 1999 (64 FR 10470), the agency 
requested comments on the proposed collections of information. No 
comments were received.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1.--Estimated Annual Reporting Burden\1\
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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
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

[[Page 40012]]

 
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 Burden\2\
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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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\2\ 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: July 15, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-18767 Filed 7-22-99; 8:45 am]
BILLING CODE 4160-01-F