[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
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CDER (amendment) 20,969 ---- .25 5,242
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CBER (amendment) 826 ---- .25 207
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CDER (annual report) 4,764 ................. .25 1,191
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CBER (annual report) 878 ................. .25 220
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CDER/CBER (new application/ ---- 214 .75 161
resubmission)
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CDRH (new application) ---- 424 .75 318
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CDER/CBER (amendment) ---- 4,451 .75 3,338
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CDRH (amendment) ---- 2,267 .75 1,700
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CDER/CBER (efficacy supplement/ ---- 259 .75 194
resubmission)
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CDER (annual report) ---- 7,753 .75 5,815
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CBER (annual report) ---- 629 .75 472
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CDER/CBER (labeling supplement) ---- 1,273 .75 955
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CDRH (supplement) ---- 2,526 .75 1,895
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CDRH (annual report) ................. 433 .75 325
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OGD (original) ................. 563 .75 422
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OGD ( BE amendment/supplement) ................. 477 .75 358
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OGD (labeling supplement) ................. 723 .75 542
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OGD (annual report) ................. 5,173 .75 3,880
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Total ................. ................. ................. 27,746
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\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