[Federal Register Volume 67, Number 156 (Tuesday, August 13, 2002)]
[Notices]
[Pages 52726-52729]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-20431]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 01N-0400]


Agency Information Collection Activities; Submission for OMB 
Review; Comment Request; Regulations Requiring Manufacturers to Assess 
the Safety and Effectiveness of New Drugs and Biological Products in 
Pediatric Patients

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 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 
September 12, 2002.

ADDRESSES: Submit written comments on the collection of information to 
the Office of Information and Regulatory Affairs, OMB, New Executive 
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: 
Stuart Shapiro, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Karen 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 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Regulations Requiring Manufacturers to Assess the Safety and 
Effectiveness of New Drugs and Biological Products in Pediatric 
Patients--(OMB Control Number 0910-0392)--Reinstatement

    FDA regulations require pediatric studies of certain new and 
marketed drugs and biological products to ensure that those products 
that are likely to be commonly used in children or that represent a 
meaningful therapeutic benefit over existing treatments contain 
adequate pediatric labeling for the approved indications at the time 
of, or soon after, approval (see 63 FR 66632, December 2, 1998). Many 
drugs and biological products represent treatments that are the best 
available treatment for children, but most of them have not been 
adequately tested in the pediatric population. As a result, product 
labeling frequently fails to provide directions for safe and effective 
use in pediatric patients. The regulations are intended to increase the 
number of drugs and biological products, with clinically significant 
use in children, that carry adequate labeling for use in that 
subpopulation. Specifically, the regulations are intended to address 
the following concerns: (1) Avoidable adverse drug reactions in 
children--drug reactions that occur because of the use of inadvertent 
drug overdoses or other drug administration problems that could have 
been avoided with better information on appropriate pediatric use; and 
(2) undertreatment of children with a potentially safe and effective 
drug because the physician either prescribed an inadequate dosage or 
regimen, prescribed a less effective drug, or did not prescribe a drug, 
due to the physician's uncertainty about whether the drug or the dose 
was safe and effective in children.
    The regulations contain the following reporting requirements that 
are subject to the PRA:
    21 CFR 201.23(a)--Manufacturers of marketed drug products submit an 
application containing data adequate to assess whether the drug product 
is safe and effective in pediatric populations; applicants develop a 
pediatric formulation for FDA approval.
    21 CFR 201.23(c)--Applicants request a full waiver of the 
requirements under Sec. 201.23(a) by certifying that necessary studies 
are impossible or highly impractical or there is evidence that the 
product would be ineffective or unsafe in all pediatric age groups. 
Applicants request a partial waiver of the requirements under 
Sec. 201.23(a) by certifying that: (1) The product does not represent a 
meaningful therapeutic benefit over existing therapies for pediatric 
patients in that age group, it is not likely to be used in a 
substantial number of patients in that age group, and the absence of 
adequate labeling could not pose significant risks to pediatric 
patients; or (2) necessary studies are impossible or highly 
impractical, or there is strong evidence that the product would be 
ineffective or unsafe in that age group, or the applicant can 
demonstrate that reasonable attempts to produce a pediatric formulation 
necessary for that age group have failed.
    21 CFR 312.47(b)(1)(iv)--Sponsors submit background information on 
the sponsor's plan for phase 3, including plans for pediatric studies, 
including a time line for protocol finalization, enrollment, 
completion, and data analysis, or information to support any

[[Page 52727]]

planned request for waiver or deferral of pediatric studies.
    21 CFR 312.47(b)(2)--Sponsors submit information on the status of 
needed or ongoing pediatric studies.
    21 CFR 314.50(d)(7)--Applicants submit a pediatric use section, 
describing the investigation of the drug for use in pediatric 
populations.
    21 CFR 314.55(a)--Applications contain data that are adequate to 
assess the safety and effectiveness of the drug product for the claimed 
indications in pediatric subpopulations and to support dosing and 
administration.
    21 CFR 314.55(b)--Applicants request a deferred submission of some 
or all assessments of safety and effectiveness required under 
Sec. 314.55(a) by certifying to the grounds for delaying pediatric 
studies, a description of planned or ongoing studies, and evidence that 
studies will be conducted at the earliest possible time.
    21 CFR 314.55(c)--Applicants request a full waiver of the 
requirements under Sec. 314.55(a) by certifying that the product does 
not represent a meaningful therapeutic benefit over existing treatments 
for pediatric patients and is not likely to be used in a substantial 
number of pediatric patients, necessary studies are impossible or 
highly impractical, or there is strong evidence that the product would 
be ineffective or unsafe in all pediatric age groups. Applicants 
request a partial waiver of the requirements under Sec. 314.55(a) by 
certifying that: (1) The product does not represent a meaningful 
therapeutic benefit over existing treatments for pediatric patients in 
that age group and it is not likely to be used in a substantial number 
of patients in that age group; (2) necessary studies are impossible or 
highly impractical; (3) there is evidence that the product would be 
ineffective or unsafe in that age group; or (4) the applicant can 
demonstrate that reasonable attempts to produce a pediatric formulation 
necessary for that age group have failed.
    21 CFR 314.81(b)(2)(i)--Applicant's annual report includes a brief 
summary of whether labeling supplements for pediatric use have been 
submitted and whether new studies in the pediatric population have been 
initiated.
    21 CFR 314.81(b)(2)(vi)(c)--Applicant's annual report includes an 
analysis of available safety and efficacy data in the pediatric 
population and changes proposed in the labeling based on this 
information.
    21 CFR 314.81(b)(2)(vii)--Applicant's annual report includes a 
status report containing a statement indicating whether postmarketing 
clinical studies in pediatric populations were required by FDA under 
Sec. 201.23, and if so, the status of these studies.
    21 CFR 601.27(a)--Applications for new biological products contain 
data that are adequate to assess the safety and effectiveness of the 
biological product for the claimed indications in pediatric 
subpopulations, and to support dosing and administration information.
    21 CFR 601.27(b)--Applicants request a deferred submission of some 
or all assessments of safety and effectiveness required under 
Sec. 601.27(a).
    21 CFR 601.27(c)--Applicants request a full waiver of the 
requirements under Sec. 601.27(a) by certifying that the product does 
not represent a meaningful therapeutic benefit over existing treatments 
for pediatric patients and is not likely to be used in a substantial 
number of pediatric patients, necessary studies are impossible or 
highly impractical, or there is strong evidence that the product would 
be ineffective or unsafe in all pediatric age groups. Applicants 
request a partial waiver of the requirements under Sec. 601.27(a) by 
certifying that: (1) The product does not represent a meaningful 
therapeutic benefit over existing treatments for pediatric patients in 
that age group and it is not likely to be used in a substantial number 
of patients in that age group; (2) necessary studies are impossible or 
highly impractical; (3) there is evidence that the product would be 
ineffective or unsafe in that age group; or (4) the applicant can 
demonstrate that reasonable attempts to produce a pediatric formulation 
necessary for that age group have failed.
    21 CFR 601.28(a)--Sponsors annually submit to FDA a brief summary 
stating whether labeling supplements for pediatric use have been 
submitted and whether new studies in the pediatric population to 
support appropriate labeling for the pediatric population have been 
initiated.
    21 CFR 601.28(b)--Sponsors submit to FDA an analysis of available 
safety and efficacy data in the pediatric population and changes 
proposed in the labeling based on this information.
    21 CFR 601.28(c)--Sponsors submit to FDA a statement on the current 
status of any postmarketing studies in the pediatric population 
performed by, or on behalf of, the applicant.
    FDA estimates that the collection of information resulting from 
these regulations is as follows:

                                   Table 1.--Estimated Annual Reporting Burden
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                                              Number of Responses    Total Annual     Hours per
 21 CFR Section    Number of Respondents        per Respondent         Responses      Response      Total Hours
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201.23(a)                    2                        1                   2             48               96
201.23(c)                    0                        0                   0              0                0
312.47(b)(1)(iv            107                        1.2               131             16            2,096
 )
312.47(b)(2)               100                        1.3               127             16            2,032
314.50(d)(7)                59                        1.3                78             50            3,900
 and 314.55(a)
314.55(b)                   60                        1.3                80             24            1,920
314.55(c)                   79                        1.3               105              8              840
314.81(b)(2)(i)            119                        1.3               158              8            1,264
314.81(b)(2)(vi            119                        1.3               158             24            3,792
 )(c)
314.81(b)(2)(vi              6                        1                   6              1.5              9
 i)
601.27(a)                    2                        1                   3             48              144
601.27(b)                    5                        1                   5             24              120
601.27(c)                    3                        1                   4              8               32
601.37(a)                   69                        1                  69              8              552
601.37(b)                   69                        1                  69             24            1,656
601.37(c)                   69                        1                  69              1.5            104
Total                                                                                                18,557
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[[Page 52728]]

    In the Federal Register of September 27, 2001 (66 FR 49389), FDA 
requested comments on the proposed collection of information. FDA 
received one comment. The comment stated, generally, that FDA 
underestimated the resources required to satisfy the collection of 
information, and requested that the agency provide a more detailed 
discussion of the assumptions and methodology used to develop the 
estimates.
    First, the comment stated that the burden to comply with the 
information collection requirements in Sec. 201.23(a) ``would involve 
hundreds of hours of development time and a variety of scientific 
specialities'' if a sponsor had to submit a supplemental application or 
a new drug application (NDA) for a pediatric formulation. The comment 
said that even if the burden for submitting a pediatric application is 
included under the other estimates in the Federal Register notice (66 
FR 49389), the burden for Sec. 201.23(a) (which ``would be limited to 
the sponsor's `opportunity for a written response and a meeting which 
may include an advisory committee meeting''') would still be greater 
than the 48 hours per response estimated by FDA.
    Second, the comment stated that FDA's estimate for compliance with 
the information collection requirements in Secs. 314.55(a) and 
601.27(a) is low ``because the collection, analysis, and reporting of 
data adequate to support pediatric use of a new drug or biological 
product * * * involves extensive resources of a multidisciplinary team 
to plan and execute the necessary clinical development program * * *.''
    Third, the comment questioned why FDA's estimate for the number of 
annual responses in Sec. 314.50(d)(7) is not equal to the estimate for 
the number of annual responses in Sec. 314.55(a), because 
``Sec. 314.50(d)(7) requires the pediatric section of an application to 
include ``information submitted under Sec. 314.55.''
    Fourth, the comment questioned why FDA did not provide a burden 
estimate for Sec. 314.50(d)(3) (human pharmacokinetics (PK) and 
bioavailability section of an application) and (d)(5) (clinical data 
section of an application).
    Fifth, the comment stated that FDA's estimate of 100 respondents 
for Sec. 314.81(b)(2)(i), (b)(2)(vi)(c), and (b)(2)(vii) is low, and 
that ``FDA might expect approximately 3,000 responses annually'' (not 
including responses from holders of approved biological license 
applications) because there are approximately 3,000 NDAs included in 
the Approved Drug Products With Therapeutic Equivalence Evaluations.
    FDA appreciates the information provided by the comment and has 
reconsidered the burden estimates in the September 27, 2001, notice.
    Concerning the question whether the numbers in table 1 (66 FR 49389 
at 49390) represent totals of all submissions since December 2, 1998, 
or whether they represent an annualized number based on the total 
received, table 1 of this document contains annualized estimates based 
on the submissions received.
    Concerning the comments on the adequacy of FDA's burden estimates 
for Secs. 201.23(a) and 314.55(a), the agency agrees that the 
collection and analysis of data adequate to support pediatric use and 
to develop a pediatric formulation would be more burdensome than the 
estimates provided in the September 27, 2001, notice. The September 27, 
2001, notice and this document, however, are part of the process to 
request that OMB extend approval for the collection of information 
described in the final rule entitled ``Regulations Requiring 
Manufacturers to Assess the Safety and Effectiveness of New Drugs and 
Biologicals Products in Pediatric Patients,'' published in the Federal 
Register of December 2, 1998 (63 FR 66632 at 66659). In the final rule 
(63 FR 66632 at 66660), FDA also estimated the costs associated with 
conducting and analyzing efficacy studies, PK studies, and new dosage 
form development. These industry costs total approximately $80 million 
annually. The analysis of the economic impact of the regulation is 
required under Executive Order 12866, the Regulatory Flexibility Act, 
and the Unfunded Mandates Reform Act. The added burden cited by the 
comment for Secs. 201.23(a) and 314.55(a) has been estimated by FDA in 
the economic analysis. Only the burden associated with compiling and 
reporting to FDA information already obtained is the subject of this 
notice and the September 27, 2001, notice. FDA published for public 
comment its initial estimate of this collection of information in the 
Federal Register of August 15, 1997 (62 FR 43900 at 43909). In the 
final rule, FDA discussed the comments on the burden estimates and 
revised the estimate for Secs. 201.23(a) and 314.55(a) from 16 hours to 
48 hours. Thus, FDA believes that the collection of information 
estimate together with the cost estimate made in the analysis of the 
economic impact of the regulation provide an adequate assessment of the 
industry burden resulting from Secs. 201.23(a) and 314.55(a).
    As a result of the comment that the number of annual responses in 
Sec. 314.50(d)(7) should be equal to the number of annual responses in 
Sec. 314.55(a), FDA has reconsidered its analysis of the collection of 
information resulting from these sections of the regulation. Under 
Sec. 314.50(d)(7), applicants must submit as part of an application and 
supplement to an approved application a ``pediatric use section.'' This 
section must describe the investigation of the drug for use in 
pediatric populations, including an integrated summary of the 
information that is relevant to the safety and effectiveness and 
benefits and risks of the drug in pediatric populations for the claimed 
indications, a reference to the full descriptions of such studies 
provided under Sec. 314.50(d)(3) and (d)(5), and information required 
to be submitted under Sec. 314.55. Under Sec. 314.55(a), applications 
must contain data that are adequate to assess the safety and 
effectiveness of the drug product for the claimed indications in all 
relevant pediatric subpopulations, and to support dosing and 
administration for each pediatric subpopulation for which the drug is 
safe and effective. FDA has determined that, for purposes of this 
collection of information analysis, the requirement to submit pediatric 
use information would more appropriately come under Sec. 314.50(d)(7). 
Section Sec. 314.55(a) is the requirement to obtain pediatric use 
information for reporting to FDA under Sec. 314.50(d)(7). Thus, FDA is 
including the reference to Sec. 314.55(a) in the same entry as 
Sec. 314.50(d)(7) in table 1 of this document. As a result of more 
recent data, FDA has revised its estimate of the number of responses 
and respondents under Sec. 314.50(d)(7). Based on the number of 
submissions to FDA of the required assessments of pediatric safety and 
effectiveness during 2001, FDA estimates that approximately 59 
applicants will submit approximately 78 assessments annually.
    Concerning the comment that FDA did not provide a burden estimate 
for Sec. 314.50(d)(3) and (d)(5), this notice and the September 27, 
2001, notice are part of the process to request that OMB extend 
approval for the collection of information described in the December 2, 
1998, final rule. The final rule did not amend Sec. 314.50(d)(3) and 
(d)(5) and, therefore, these sections were not included in the 
collection of information analysis in the final rule. The information 
collection under Sec. 314.50(d)(3) and (d)(5), as well as other 
provisions under 21 CFR part 314, are already approved by OMB until

[[Page 52729]]

November 30, 2004, under OMB control number 0910-0001.
    The comment also stated that FDA's estimate of 100 respondents for 
Sec. 314.81(b)(2)(i), (b)(2)(vi)(c), and (b)(2)(vii) is low, and that 
over 3,000 responses should be expected annually. Under these sections, 
applicants must submit in their annual report: (1) A brief summary of 
whether labeling supplements for pediatric use have been submitted and 
whether new studies in the pediatric population have been initiated; 
(2) an analysis of available safety and efficacy data in the pediatric 
population and changes proposed in the labeling based on this 
information; and (3) a status report containing a statement indicating 
whether postmarketing clinical studies in pediatric populations were 
required by FDA under Sec. 201.23, and if so, the status of these 
studies. Thus, only the annual reports for those approved applications 
that contain or will contain pediatric use information would be covered 
by these sections. As a result of more recent data, FDA has revised its 
estimates of the number of responses and respondents for these 
sections. Based on the number of currently approved applications and 
the number of pending applications that contain pediatric use 
information, FDA estimates approximately 119 applicants will submit 
approximately 158 annual reports under Sec. 314.81(b)(2)(i), 
approximately 119 applicants will submit approximately 158 annual 
reports under Sec. 314.81(b)(2)(vi)(c), and approximately 6 applicants 
will submit approximately 6 annual reports under 
Sec. 314.81(b)(2)(vii).
    As a result of more recent FDA data on the number of requests for 
deferrals and waivers received by the agency in 2001, FDA has also 
revised the estimates for Sec. 314.55(b) and (c) as reflected in the 
table 1 of this document.

    Dated: August 6, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-20431 Filed 8-12-02; 8:45 am]
BILLING CODE 4160-01-S