[Federal Register Volume 73, Number 165 (Monday, August 25, 2008)]
[Notices]
[Pages 50024-50028]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-19625]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-N-0144]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Certification to 
Accompany Drug, Biological Product, and Device Applications or 
Submissions (Form FDA 3674)

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that a 
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.

DATES: Fax written comments on the collection of information by 
September 24, 2008.

ADDRESSES: To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, 
FAX: 202-395-6974, or e-mailed to [email protected]. All comments 
should be identified with the OMB control number 0910-0616. Also 
include the FDA docket number found in brackets in the heading of this 
document.

FOR FURTHER INFORMATION CONTACT: Jonna Capezzuto, Office of Information 
Management (HFA-710), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-796-3794.

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.

Certification to Accompany Drug, Biological Product, and Device 
Applications or Submissions (Form FDA 3674) (OMB Control Number 0910-
0616) -- Extension

    The information required under section 402(j)(5)(B) of the Public 
Health Service Act (PHS Act) (42 U.S.C. 282(j)(5)(B)) will be submitted 
in the form of a certification to accompany applications and 
submissions currently submitted to FDA under part 312 (21

[[Page 50025]]

CFR part 312) and 21 CFR part 314 (human drugs) and approved under OMB 
control numbers 0910-0014 (expires May 31, 2009) and 0910-0001 (expires 
May 31, 2011), respectively; submitted to FDA under part 312 and 21 CFR 
part 601 (biological products) and approved under OMB control numbers 
0910-0014 and 0910-0338 (expires June 30, 2010); and submitted to FDA 
under 21 CFR parts 807 and 814 (devices) and approved under OMB control 
numbers 0910-0120 (expires August 31, 2010) and 0910-0231 (expires 
November 30, 2010), respectively.
    Title VIII of the Food and Drug Administration Amendments Act of 
2007 (FDAAA) (Public Law 110-85) amended the PHS Act by adding section 
402(j) (42 U.S.C. 282(j)). The new provisions require additional 
information to be submitted to the clinical trials data bank 
(ClinicalTrials.gov)\1\ previously established by the National 
Institutes of Health/National Library of Medicine, including expanded 
information on clinical trials and information on the results of 
clinical trials. The provisions include new responsibilities for FDA as 
well as several amendments to the Federal Food, Drug, and Cosmetic Act 
(FD&C Act).
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    \1\ FDA has verified the Web site address, but FDA is not 
responsible for any subsequent changes to the Web site after this 
document publishes in the Federal Register.
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    One new provision, section 402(j)(5)(B) of the PHS Act, requires 
that a certification accompany human drug, biological, and device 
product submissions made to FDA. Specifically, at the time of 
submission of an application under sections 505, 515, or 520(m) of the 
FD&C Act (21 U.S.C. 355, 360e, or 360j(m)), or under section 351 of the 
PHS Act (42 U.S.C. 262), or submission of a report under section 510(k) 
of the FD&C Act (21 U.S.C. 360(k)), such application or submission must 
be accompanied by a certification that all applicable requirements of 
section 402(j) of the PHS Act have been met. Where available, such 
certification must include the appropriate National Clinical Trial 
(NCT) numbers.
    The proposed collection of information is necessary to satisfy the 
previously mentioned statutory requirement.
    The importance of obtaining these data relates to adherence to the 
legal requirements for submissions to the clinical trials registry and 
results data bank and ensuring that individuals and organizations 
submitting applications or reports to FDA under the listed provisions 
of the FD&C Act or the PHS Act adhere to the appropriate legal and 
regulatory requirements for certifying to having complied with those 
requirements. The failure to submit the certification required by 
section 402(j)(5)(B) of the PHS Act, and the knowing submission of a 
false certification are both prohibited acts under section 301 of the 
FD&C Act (21 U.S.C. 331). Violations are subject to civil money 
penalties.

Investigational New Drug Applications

    FDA's Center for Drug Evaluation and Research (CDER) received 1,837 
investigational new drug applications (INDs) and 20,969 new IND 
amendments in Fiscal Year (FY) 2004. CDER received 4,764 annual reports 
in FY 2004. CDER anticipates that IND, amendment, and annual report 
submission rates will remain at or near this level in the near future.
    FDA's Center for Biologics Evaluation and Research (CBER) received 
206 new INDs and 826 new IND amendments in FY 2004. CBER received 878 
annual reports in FY 2004. CBER anticipates that IND, amendment, and 
annual report submission rates will remain at or near this level in the 
near future.
    The estimated total number of submissions (new INDs, new 
submissions, and annual reports) subject to mandatory certification 
requirements under 42 U.S.C. 282(j)(5)(B), section 402(j)(5)(B) of the 
PHS Act, is 27,570 for CDER plus 1,910 for CBER, or 29,480 submissions 
per year. The minutes per response is the estimated number of minutes 
that a respondent would spend preparing the information to be submitted 
to FDA under 42 U.S.C. 282(j)(5)(B), section 402(j)(5)(B) of the PHS 
Act, including the time it takes to type the necessary information.
    Based on its experience reviewing INDs and consideration of the 
previous information, FDA estimated that approximately 15.0 minutes on 
average would be needed per response for certifications which accompany 
IND applications and submissions. It is assumed that most submissions 
to investigational applications will reference only a few protocols for 
which the sponsor/applicant/submitter has obtained a National Clinical 
Trial (NCT) number from ClinicalTrials.gov prior to making the 
submission to FDA. It is also assumed that the sponsor/applicant/
submitter has electronic capabilities allowing them to retrieve the 
information necessary to complete the form in an efficient manner.

Marketing Applications/Submissions

    In 2004, CDER and CBER received 214 new drug applications (NDA)/
biologics license applications (BLA)/resubmissions and 4,451 NDA/BLA 
amendments for which certifications are needed. CDER and CBER received 
259 efficacy supplements/resubmissions to previously approved NDAs/
BLAs, and 1,273 labeling submissions in FY 2004. CDER received 7,753 
annual reports and CBER received 629 annual reports in FY 2004. CDER 
and CBER anticipate that new drug/biologic, efficacy supplement, and 
annual report submission rates will remain at or near this level in the 
near future.
    FDA's Center for Devices and Radiological Health (CDRH) received 51 
new applications for premarket approvals (PMA), 364 510(k) submissions 
containing clinical information, and 9 applications for humanitarian 
device exemptions (HDE), for a total of 424 new applications/
submissions in FY 2004. CDRH received 2,267 PMA/510(k)/HDE amendments 
in FY 2004. CDRH received 2,526 PMA/510(k)/HDE supplements in FY 2004. 
CDRH received 433 annual reports in FY 2004. CDRH anticipates that 
application, amendment, supplement, and annual report submission rates 
will remain at or near this level in the near future.
    FDA's Office of Generic Drugs (OGD) received 563 abbreviated new 
drug applications (ANDAs) in FY 2004. OGD received 477 bioequivalence 
amendments/supplements and 723 labeling supplements in FY 2004. OGD 
received 5,173 annual reports in FY 2004. OGD anticipates that 
application, amendment, supplement, and annual report submission rates 
will remain at or near this level in the near future.
    The estimated total number of new submissions (new marketing 
applications/submissions, amendments, supplements, and annual reports) 
subject to the mandatory certification requirements under 42 U.S.C. 
282(j)(5)(B), section 402(j)(5)(B) of the PHS Act, is 14,579 for CDER 
and CBER, 5,650 for CDRH, plus 6,936 for OGD or 27,165 new submissions 
per year. The minutes per response is the estimated number of minutes 
that a respondent would spend preparing the information to be submitted 
to FDA under 42 U.S.C. 282(j)(5)(B), section 402(j)(5)(B) of the PHS 
Act, including the time it takes to type the necessary information and 
compile a list of relevant NCT numbers.
    Based on its experience reviewing NDAs, BLAs, PMAs, HDEs, 510(k)s, 
and ANDAs and consideration of the previous information, FDA estimated

[[Page 50026]]

that approximately 45.0 minutes on average would be needed per response 
for certifications which accompany NDA, BLA, PMA, HDE, 510(k), and ANDA 
applications and submissions. It is assumed that the sponsor/applicant/
submitter has electronic capabilities allowing them to retrieve the 
information necessary to complete the form in an efficient manner.
    In the Federal Register of March 5, 2008 (73 FR 11926), FDA 
published a 60-day notice requesting public comment on the information 
collection provisions. FDA received a number of comments concerning 
such issues as FDA's legal interpretation of the statutory language, 
clarification of the instructions to the form, concerns with FDA's 
estimates of the amount of time required to fill out the form, and 
suggestions for technical formatting changes to the form.
    (Comment 1) A number of respondents maintained that, because 
section 402(j)(5)(B) of the PHS Act does not apply to INDs submitted to 
FDA under section 505(i) of the FD&C Act, a certification form need not 
accompany INDs submitted to FDA. As previously stated, section 
402(j)(5)(B) of the PHS Act, requires that, at the time of submission 
of an application under sections 505, 515, or 520(m) of the FD&C Act 
(21 U.S.C. 355, 360e, or 360j(m)), or under section 351 of the PHS Act 
(42 U.S.C. 262), or submission of a report under section 510(k) of the 
FD&C Act (21 U.S.C. 360(k)), such application or submission must be 
accompanied by a certification that all applicable requirements of 
section 402(j) of the PHS Act have been met. The comments challenge the 
agency's interpretation of Section 402(j)(5)(B) of the PHS Act on 
several fronts. The respondents maintain that IND submissions are not 
``applications'' in the terminology of the FD&C Act. Some comments rely 
upon language found in HR 2900, an earlier version of the legislation 
that was eventually enacted as FDAAA, to support their assertion that 
Congress both understood the distinction between ``applications'' on 
the one hand, and ``submissions'' and ``exemptions'' on the other, and 
that Congress explicitly omitted exemptions from the scope of the 
certification requirement. The language in HR 2900 would have required 
the FDA to verify that the requirements of section 402(j) were met for 
each applicable clinical trial submitted when considering a drug for an 
exemption under section 505(i). Section 402(j) no longer includes this 
verification requirement, and the explicit reference to section 505(i) 
in HR 2900 was omitted from section 402(j)(5)(B) of the PHS Act. 
Commenters further stated that submitting a certification of compliance 
when submitting an IND is illogical because an IND must be submitted to 
FDA prior to enrolling subjects in the clinical trials, yet 
registration in the clinical trials data bank is not generally required 
until 21 days after the first subject is enrolled in the clinical 
trial. In addition, some of the comments noted that the conforming 
amendment to section 505(i) of the FD&C Act relates only to informed 
consent documentation and includes no reference to the certification 
requirement.
    (Response) FDA does not agree with these conclusions. FDA agrees 
that the word ``application'' is not used in section 505(i) of the FD&C 
Act in reference to an IND. However, section 505(i)(1) directed the 
Secretary of Health and Human Services to issue regulations exempting 
from the requirements of section 505 of the FD&C Act drugs intended 
solely for investigational use. The regulations issued by FDA under 
this authority define an IND as ``an investigational new drug 
application.'' 21 CFR 312.3 (emphasis added). Furthermore, these 
regulations repeatedly use the term ``application'' in reference to an 
IND. Therefore, FDA considers an IND to be an application under section 
505 of the FD&C Act . Congress is familiar with FDA regulations and 
could have specifically exempted INDs from the certification process by 
directly excluding 505(i) from the scope of section 402(j)(5)(B) of the 
PHS Act.
    FDA disagrees with the commenters' conclusions that the precursor 
language in HR 2900 demonstrates that Congress intended to exclude INDs 
from the certification requirement and that Congress understood the 
difference between marketing applications and IND submissions and 
exemptions. FDA has concluded that the reference to section 505 of the 
FD&C Act was simply a streamlined reference to all applications and 
submissions possible under section 505 of the FD&C Act. The scope of 
Title VIII of FDAAA, the numerous requirements for updating the 
clinical trials registry information, the inclusion of a new clinical 
trials results data bank, and the new enforcement provisions (including 
making failure to file a certification a prohibited act) indicate that 
Congress intended that the clinical trials data bank include 
information about clinical trials throughout the product development 
life cycle. Clearly, the IND phase is an extremely important phase of 
this process. The certification required by section 402(j)(5)(B) of the 
PHS Act is one means of ensuring that the clinical trial registry 
information is submitted when required. This information is required to 
be submitted to the registry data bank well before an NDA is ever filed 
with FDA. If the certification did not accompany INDs, there would be 
no means of ensuring that information is submitted to the registry data 
bank during the investigational stage, which would be inconsistent with 
the statute's intent to have such information available.
    Further, submission of the certification with INDs helps to ensure 
that the clinical trial information is submitted to the registry data 
bank for trials that are never submitted in an NDA or a BLA. Many 
trials are never submitted in an NDA or a BLA. Requiring that the 
certification accompany INDs helps ensure that applicable clinical 
trials that are not included in an NDA or BLA are registered as 
required. The fact that an original IND application is filed with FDA 
before the responsible party is required to register a trial does not 
require the conclusion that certifications were intended to be 
inapplicable to INDs. Throughout the life of an IND, there are numerous 
opportunities for filing IND amendments, many of which will be filed 
after the trial is required to be registered. Submission of the 
certification with these IND amendments helps to ensure that the 
requirements of section 402(j) of the PHS Act are met.
    The lack of a conforming amendment for INDs is not an indicator 
that certifications are not required to be submitted with INDs. There 
is also no conforming amendment for BLAs, but it is clear from the 
wording of section 402(j)(5)(B) of the PHS Act that the certification 
is required to be submitted with applications under section 351 of the 
PHS Act. The statute must be considered in its entirety; in light of 
the other provisions of the statute discussed in the previous 
paragraph, and the language of section 402(j)(5)(B), FDA has concluded 
that the absence of those two conforming amendments does not detract 
from the statutory language requiring submission of a certification 
when submitting an application under section 505 of the FD&C Act (or 
when submitting a BLA under section 351 of the PHS Act). Accordingly, 
FDA concludes that the certification form should accompany INDs.
    (Comment 2) A number of comments challenged FDA's conclusion that 
the term ``application'' refers to supplements, annual reports, or 
adverse event reports.

[[Page 50027]]

    (Response) The term ``application'' is used in the context of many 
filings made with FDA, particularly with products handled by CDER and 
CBER. Supplements, annual reports, and other submissions are all 
characterized as ``applications'' by FDA and are identified as such 
throughout parts 312 and 314 of FDA's regulations. For example, the 
form with which sponsors submit most IND, NDA, and BLA-related 
submissions is the Form FDA 356h, which is titled ``Application to 
Market a New Drug, Biologic, or an Antibiotic Drug for Human Use,'' 
includes check boxes for submitting, among other things, annual 
reports, efficacy supplement, labeling supplement and chemistry 
manufacturing and controls supplement. As stated previously, FDA 
assumes that Congress was familiar with FDA regulations when it drafted 
section 402(j) of the PHS Act.
    FDA appreciates that there are many routine filings that fall under 
this broader definition of application; however, the relevant statutory 
language is itself written very broadly. FDA recognizes the burden 
associated with submitting certifications with all of these filings, 
and FDA continues to work to identify filings which may not need to be 
accompanied by a certification. In April 2008, FDA issued a draft 
guidance describing FDA's current thinking on the types of information 
and documents that need not be accompanied by a certification. (See, 
Guidance For Sponsors, Industry, Researchers, Investigators, and Food 
And Drug Administration Staff: Certifications To Accompany Drug, 
Biological Product, And Device Applications/Submissions: Compliance 
With Section 402(J) of The Public Health Service Act, Added By Title 
VIII of The Food And Drug Administration Amendments Act of 2007, April 
2008, available at http://www.fda.gov/oc/initiatives/fdaaa/guidance_certifications.html).
    FDA will address any suggestions made by the respondents that are 
relevant to the issues contained in the draft guidance when FDA 
finalizes that draft guidance.
    (Comment 3) A number of comments concerned the burden estimate and 
stated that FDA underestimated the amount of time needed to prepare the 
form. Related to these comments were comments that requested the form 
be PDF fillable; that it be able to be electronically saved in order to 
be used repeatedly; and/or that the form be combined with other 
existing forms.
    (Response) In evaluating the burden, FDA considered the fact that 
multiple certifications relating to a single IND or NDA may be filed 
with FDA. FDA anticipated that many submitters would pre-fill and save 
electronic versions of the forms necessary for existing applications. 
When an NCT number becomes available or a new one is issued related to 
a particular application, it then can simply be added to the previously 
completed form. Although the draft certification form was not PDF 
fillable and was not able to be saved electronically, the form 
currently is PDF fillable and is able to be saved electronically, which 
means it can be amended by submitters as necessary. FDA further 
determined that, over time, familiarity with the form and the 
requirements of section 402(j) of the PHS Act would significantly 
reduce the amount of time needed to prepare the form for filing.
    With regard to the suggestion that the certification be 
incorporated into existing forms, section 402(j)(5) of the PHS Act 
requires that the certification ``accompany'' an application or 
submission, and we infer from this wording that the certification is 
not intended to be part of that application or submission. Because the 
existing forms are considered to be part of the application or 
submission, it is not appropriate to add the certification to those 
forms. FDA notes, however, that it is possible that, as FDA's 
information technology systems continue to evolve, more forms and 
submissions will be filed electronically, and there will be a means to 
transfer information from an application onto the certification form.
    (Comment 4) One comment requested that the form be modified to 
remove the second sentence above the signature block. The second 
sentence currently reads: ``Warning: A willfully and knowingly false 
statement is a criminal offense, U.S. Code, title 18, section 1001.'' 
The rationale for requesting removal of the sentence was that ``FDAAA 
does not authorize FDA to bring a perjury action for failure to certify 
accurately.''
    (Response) The sentence requested to be removed does not entail a 
perjury charge. In the draft certification form circulated for comment 
in December 2007, FDA did include a sentence that indicated a charge of 
perjury could be brought. After further consideration of the statute 
and the certification form, FDA concluded that this sentence should be 
removed. However, the knowing and willful inclusion of a materially 
false statement in any government document is subject to 18 U.S.C. 
1001, which allows a criminal charge to be brought for violations of 
that section. Accordingly, this reference to 18 U.S.C. 1001 will not be 
removed from the form.
    (Comment 5) A number of respondents commented that the 
certification should apply only to clinical trials sponsored by the 
applicant and the form should not require certification with regard to 
trials over which the manufacturer/sponsor had no control.
    (Response) The certification provision, section 402(j)(5)(B) of the 
PHS Act, does not make a distinction between trials conducted by the 
sponsor and trials relied upon in the application but conducted by 
entities other than the sponsor. FDA is aware that sponsors or 
applicants will be required to certify as to trials they did not 
conduct or register in the clinical trials data bank. FDA has addressed 
this concern by requiring the submitter to declare that the information 
submitted is accurate, true, and complete ``to the best of her/his 
knowledge.''
    (Comment 6) Respondents made a number of miscellaneous suggestions 
related to the certification form such as changing the FDA Form 3674 to 
eliminate sections 9.A and 9.B.; clarifying the certification form's 
instructions; and updating the eCTD (electronic common technical 
document) specifications to account for the certification form.
    (Response) At the current time, the form will remain the same. The 
boxes 9.A and 9.B in the certification form will not be removed. These 
boxes provide information allowing FDA to determine if there are 
clinical trials referenced in the application /submission to which the 
requirements of section 402(j) of the PHS Act apply without having to 
review each clinical trial included in the application or submission. 
However, we have updated the instructions to provide additional clarity 
for sponsors in filling out the information required. Lastly, as the 
eCTD specifications are updated, FDA intends to consider adding an 
appropriate leaf module for the certification form.
    Estimated Annual Reporting Burden
    Table 1 of this document provides an estimate of the annual 
reporting burden for the submission of information to satisfy the 
requirements of section 402(j)(5)(B) of the PHS Act. The annual 
reporting burden reflects changes made based on certain applications/
submissions either removed from the burden calculations made in the 
original estimates or new applications/submissions added to the burden 
calculations. Those applications/submissions removed include those we 
currently have determined do not

[[Page 50028]]

typically require that a certification form accompany the application/
submission, as described in our April 2008 Draft Guidance. Added to the 
burden were generic applications/submissions, which were originally not 
included in the burden calculations, but have since been determined to 
require a certification form accompany the application/submission.

                                 Table 1.--Estimated Annual Reporting Burden\1\
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                                       Investigational       Marketing          Hours per
                                         Applications       Applications         Response         Total Hours
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CDER (new application)                            1,837               ----                .25                459
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CBER (new application)                              206               ----                .25                 52
----------------------------------------------------------------------------------------------------------------
CDER (amendment)                                 20,969               ----                .25              5,242
----------------------------------------------------------------------------------------------------------------
CBER (amendment)                                    826               ----                .25                207
----------------------------------------------------------------------------------------------------------------
CDER (annual report)                              4,764  .................                .25              1,191
----------------------------------------------------------------------------------------------------------------
CBER (annual report)                                878  .................                .25                220
----------------------------------------------------------------------------------------------------------------
CDER/CBER (new application/                        ----                214                .75                161
 resubmission)
----------------------------------------------------------------------------------------------------------------
CDRH (new application)                             ----                424                .75                318
----------------------------------------------------------------------------------------------------------------
CDER/CBER (amendment)                              ----              4,451                .75              3,338
----------------------------------------------------------------------------------------------------------------
CDRH (amendment)                                   ----              2,267                .75              1,700
----------------------------------------------------------------------------------------------------------------
CDER/CBER (efficacy supplement/                    ----                259                .75                194
 resubmission)
----------------------------------------------------------------------------------------------------------------
CDER (annual report)                               ----              7,753                .75              5,815
----------------------------------------------------------------------------------------------------------------
CBER (annual report)                               ----                629                .75                472
----------------------------------------------------------------------------------------------------------------
CDER/CBER (labeling supplement)                    ----              1,273                .75                955
----------------------------------------------------------------------------------------------------------------
CDRH (supplement)                                  ----              2,526                .75              1,895
----------------------------------------------------------------------------------------------------------------
CDRH (annual report)                  .................                433                .75                325
----------------------------------------------------------------------------------------------------------------
OGD (original)                        .................                563                .75                422
----------------------------------------------------------------------------------------------------------------
OGD ( BE amendment/supplement)        .................                477                .75                358
----------------------------------------------------------------------------------------------------------------
OGD (labeling supplement)             .................                723                .75                542
----------------------------------------------------------------------------------------------------------------
OGD (annual report)                   .................              5,173                .75              3,880
----------------------------------------------------------------------------------------------------------------
Total                                 .................  .................  .................            27,746
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    We believe the estimate of 27,746 hours per year accurately 
reflects the burden. We recognize that individuals or entities less 
familiar with FDA forms and the clinical trials data bank 
(ClinicalTrials.gov) may require greater than 15 and 45 minutes 
(depending on the type of application/submission) per response.

    Dated: August 19, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-19625 Filed 8-22-08; 8:45 am]
BILLING CODE 4160-01-S