[Federal Register Volume 65, Number 4 (Thursday, January 6, 2000)]
[Notices]
[Pages 779-782]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-236]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 99D-0529]
Agency Information Collection Activities: Proposed Collection;
Comment Request
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing an
opportunity for public comment on the proposed collection of certain
information by the agency. Under the Paperwork Reduction Act of 1995
(the PRA), Federal agencies are required to publish notice in the
Federal Register concerning each proposed collection of information,
and to allow 60 days for public comment in response to the notice. This
notice solicits comments on the collection of information contained in
a guidance for industry entitled ``Changes to an Approved NDA or
ANDA.'' The guidance is intended to assist applicants in determining
how they should report changes to an approved new drug application
(NDA) or abbreviated new drug application (ANDA) under section 116 of
the Food and Drug Administration Modernization Act (the Modernization
Act), which provides requirements for making and reporting
manufacturing changes to an approved application and for distributing a
drug product made with such changes.
DATES: Submit written comments on the collection of information by
March 6, 2000.
ADDRESSES: Submit written comments on the collection of information to
the Dockets Management Branch (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should
be identified with the docket number found in brackets in the heading
of this document.
FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information
Resources Management (HFA-250), Food and Drug Administration, 5600
[[Page 780]]
Fishers Lane, Rockville, MD 20857, 301-827-1482.
SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal
agencies must obtain approval from the Office of Management and Budget
(OMB) for each collection of information they conduct or sponsor.
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes agency requests or requirements that members of
the public submit reports, keep records, or provide information to a
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A))
requires Federal agencies to provide a 60-day notice in the Federal
Register concerning each proposed collection of information, before
submitting the collection to OMB for approval. To comply with this
requirement, FDA is publishing notice of the proposed collection of
information listed below.
With respect to the following collection of information, FDA
invites comments on: (1) Whether the proposed collection of information
is necessary for the proper performance of FDA's functions, including
whether the information will have practical utility; (2) the accuracy
of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Guidance for Industry: Changes to an Approved NDA or ANDA
On November 21, 1997, the President signed into law the
Modernization Act (Public Law 105-115). Section 116 of the
Modernization Act amended the Federal Food, Drug, and Cosmetic Act (the
act) by adding section 506A (21 U.S.C. 356a), which describes
requirements and procedures for making and reporting manufacturing
changes to approved new drug and ANDAs', to new and abbreviated animal
drug applications, and to license applications for biological products.
The guidance provides recommendations to holders of approved new
drug and ANDA's who intend to make postapproval changes in accordance
with section 506A of the act. The guidance covers recommended reporting
categories for postapproval changes for drugs, other than specified
biotechnology and specified synthetic biological products.
Recommendations are provided for postapproval changes in: (1)
Components and composition, (2) sites, (3) manufacturing process, (4)
specification(s), (5) package, (6) labeling, and (7) miscellaneous
changes.
Section 116 of the Modernization Act amended the act by adding
section 506A, which includes the following provisions:
1. A drug made with a manufacturing change, whether a major
manufacturing change or otherwise, may be distributed only after the
applicant validates the effects of the change on the identity,
strength, quality, purity, and potency of the drug as these factors may
relate to the safety or effectiveness of the drug (section 506A(a)(1)
and (b) of the act). This section recognizes that additional testing,
beyond testing to ensure that an approved specification is met, is
required to ensure unchanged identity, strength, quality, purity, or
potency as these factors may relate to the safety or effectiveness of
the drug.
2. A drug made with a major manufacturing change may be
distributed only after the applicant submits a supplemental application
to FDA and the supplemental application is approved by the agency. The
application is required to contain information determined to be
appropriate by FDA and include the information developed by the
applicant when ``validating the effects of the change'' (section
506A(c)(1) of the act).
3. A major manufacturing change is a manufacturing change
determined by FDA to have substantial potential to adversely affect the
identity, strength, quality, purity, or potency of the drug as these
factors may relate to the safety or effectiveness of the drug. Such
changes include: (1) A change made in the qualitative or quantitative
formulation of the drug involved or in the specifications in the
approved application or license unless exempted by FDA by regulation or
guidance; (2) a change determined by FDA by regulation or guidance to
require completion of an appropriate clinical study demonstrating
equivalence of the drug to the drug manufactured without the change;
and (3) other changes determined by FDA by regulation or guidance to
have a substantial potential to adversely affect the safety or
effectiveness of the drug (section 506A(c)(2) of the act).
4. FDA may require submission of a supplemental application for
drugs made with manufacturing changes that are not major (section
506A(d)(1)(B) of the act) and establish categories of manufacturing
changes for which a supplemental application is required (section
506A(d)(1)(C) of the act). In such a case the applicant may begin
distribution of the drug 30 days after FDA receives a supplemental
application unless the agency notifies the applicant within the 30-day
period that prior approval of the application is required (section
506A(d)(3)(B)(i) of the act). FDA may also designate a category of
manufacturing changes that permit the applicant to begin distributing a
drug made with such changes upon receipt by the agency of a
supplemental application for the change (section 506A(d)(3)(B)(ii) of
the act). If FDA disapproves a supplemental application, the agency may
order the manufacturer to cease the distribution of drugs that have
been made with the disapproved change (section 506A(d)(3)(B)(iii) of
the act).
5. FDA may authorize applicants to distribute drugs without
submitting a supplemental application (section 506A(d)(1)(A) of the
act) and may establish categories of manufacturing changes that may be
made without submitting a supplemental application (section
506A(d)(1)(C) of the act). The applicant is required to submit a report
to FDA on such a change and the report is required to contain
information the agency deems to be appropriate and information
developed by the applicant when validating the effects of the change.
FDA may also specify the date on which the report is to be submitted
(section 506A(d)(2)(A) of the act). If during a single year an
applicant makes more than one manufacturing change subject to an annual
reporting requirement, FDA may authorize the applicant to submit a
single report containing the required information for all the changes
made during the year (annual report) (section 506A(d)(2)(B) of the
act).
Section 506A of the act provides FDA with considerable flexibility
to determine the information and filing mechanism required for the
agency to assess the effect of manufacturing changes in the safety and
effectiveness of the product. There is a corresponding need to retain
such flexibility in the guidance on section 506A of the act to ensure
that the least burdensome means for reporting changes are available.
FDA believes that such flexibility will allow it to be responsive to
increasing knowledge of and experience with certain types of changes
and help ensure the efficacy and safety of the products involved. For
example, a change that may currently be considered to have a
substantial potential to have an adverse effect on the safety or
effectiveness of the product may, at a later date, based on new
information or advances in technology, be determined to have a
[[Page 781]]
lesser potential to have such an adverse effect. Conversely, a change
originally considered to have a minimal or moderate potential to have
an adverse effect on the safety or effectiveness of the product may
later, as a result of new information, be found to have an increased,
substantial potential to adversely affect the product. The guidance
enables the agency to respond more readily to knowledge gained from
manufacturing experience, further research and data collection, and
advances in technology. The guidance describes the agency's current
interpretation of specific changes falling into the four filing
categories. Section 506A of the act explicitly provides FDA the
authority to use guidance documents to determine the type of changes
that do or do not have a substantial potential to adversely affect the
safety or effectiveness of the drug product. The use of guidance
documents allows FDA to more easily and quickly modify and update
important information.
FDA estimates the burden of this collection of information as
follows:
Table 1.--Estimated Annual Reporting Burden1
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Number of
Federal Food, Drug, and Cosmetic Number of Responses per Total Annual Hours per Total Hours
Act Section Respondents Respondent Responses Response
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506A(c)(1) and (c)(2) 594 3 1,744 120 209,280
Prior Approval Supp.
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506A(d)(1)(B), (d)(1)(C), and 594 5 2,754 80 220,320
(d)(3)(B)(i)
CBE in 30-days Supp.
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506A(d)(1)(B), (d)(1)(C), and 486 1 486 80 38,880
(d)(3)(B)(ii)
CBE Supp.
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506A(d)(1)(A), (d)(1)(C), 704 10 6,929 25 173,225
(d)(2)(A), and (d)(2)(B)
Annual Report
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Total 641,705
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
Section 506A(a)(1) and (b) of the act requires the holder of an
approved application to validate the effects of a manufacturing change
on the identity, strength, quality, purity, or potency of the drug as
these factors may relate to the safety or effectiveness of the drug
before distributing a drug made with the change. Under section
506A(d)(3)(A) of the act, information developed by the applicant to
validate the effects of the change regarding identity, strength,
quality, purity, and potency is required to be submitted to FDA as part
of the supplement or annual report. Thus, no separate estimates are
provided for these sections in Table 1 of this document; estimates for
validation requirements are included in the estimates for supplements
and annual reports. The guidance does not provide recommendations on
the specific information that should be developed by the applicant to
validate the effect of the change on the identity, strength (e.g.,
assay, content uniformity), quality (e.g., physical, chemical, and
biological properties), purity (e.g., impurities and degradation
products), or potency (e.g., biological activity, bioavailability,
bioequivalence) of a product as they may relate to the safety or
effectiveness of the product.
Section 506A(c)(1) and (c)(2) of the act sets forth requirements
for changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes).
Under this section, a supplement must be submitted for any change in
the product, production process, quality controls, equipment, or
facilities that has a substantial potential to have an adverse effect
on the identity, strength, quality, purity, or potency of the product
as these factors may relate to the safety or effectiveness of the
product. The applicant must obtain approval of a supplement from FDA
prior to distribution of a product made using the change.
Based on data concerning the number of supplements received by the
agency, FDA estimates that approximately 1,744 supplements will be
submitted annually under section 506A(c)(1) and (c)(2) of the act. FDA
estimates that approximately 594 applicants will submit such
supplements, and that it will take approximately 120 hours to prepare
and submit to FDA each supplement.
Section 506A(d)(1)(B), (d)(1)(C), and (d)(3)(B)(i) of the act sets
forth requirements for changes requiring supplement submission at least
30 days prior to distribution of the product made using the change
(moderate changes). Under this section, a supplement must be submitted
for any change in the product, production process, quality controls,
equipment, or facilities that has a moderate potential to have an
adverse effect on the identity, strength, quality, purity, or potency
of the product as these factors may relate to the safety or
effectiveness of the product. Distribution of the product made using
the change may begin not less than 30 days after receipt of the
supplement by FDA.
Based on the data concerning the number of supplements received by
the agency, FDA estimates that approximately 2,754 supplements will be
submitted annually under section 506A(d)(1)(B), (d)(1)(C), and
(d)(3)(B)(i) of the act. FDA estimates that approximately 594
applicants will submit such supplements, and that it will take
approximately 80 hours to prepare and submit to FDA each supplement.
Under section 506A(d)(3)(B)(ii) of the act, FDA may designate a
category of changes for the purpose of providing that, in the case of a
change in such category, the holder of an approved application may
commence distribution of the drug upon receipt by the agency of a
supplement for the change. Based on the data concerning the number of
supplements received by the agency, FDA estimates that approximately
486 supplements will be submitted annually under section
506A(d)(3)(B)(ii) of the act. FDA estimates that approximately 486
applicants will submit such supplements, and that it will take
approximately 80 hours to prepare and submit to FDA each supplement.
[[Page 782]]
Section 506A(d)(1)(A), (d)(1)(C), (d)(2)(A), and (d)(2)(B) of the
act sets forth requirements for changes to be described in an annual
report (minor changes). Under this section, changes in the product,
production process, quality controls, equipment, or facilities that
have a minimal potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as these factors
may relate to the safety or effectiveness of the product must be
documented by the applicant in the next annual report.
Based on the data concerning the number of supplements and annual
reports received by the agency, FDA estimates that approximately 6,929
annual reports will include documentation of certain manufacturing
changes as required under section 506A(d)(1)(A), (d)(1)(C), (d)(2)(A),
and (d)(2)(B) of the act. FDA estimates that approximately 704
applicants will submit such information, and that it will take
approximately 25 hours to prepare and submit to FDA the information for
each annual report.
In the Federal Register of June 28, 1999 (64 FR 34608), FDA
published a proposed rule to implement section 116 of the Modernization
Act by revising current regulations at Sec. 314.70 (21 CFR 314.70) on
supplements and other changes to an approved application. In that same
issue of the Federal Register (64 FR 34660), FDA published a notice of
availability of a draft guidance for industry entitled ``Changes to an
Approved NDA or ANDA.'' On August 19, 1999, FDA held a public meeting
to discuss and receive comments on the proposed regulations and the
draft guidance (64 FR 42625, August 5, 1999).
The period for public comment on the proposed regulations closed
on September 13, 1999, and FDA is currently reviewing the comments and
preparing a final rule. The comment period for the draft guidance
closed on August 27, 1999, and FDA has considered these comments when
preparing the guidance that is the subject of this request.
In the Federal Register of November 23, 1999 (64 FR 65176), FDA
requested emergency processing of this proposed collection of
information under section 3507(j) of the PRA and 5 CFR 1320.13. The
information is needed immediately to implement section 506A of the act.
The use of normal information clearance procedures would likely result
in the prevention or disruption of this collection of information
because section 506A of the act takes effect on November 21, 1999.
After November 20, 1999, and until final regulations are promulgated
revising Sec. 314.70, section 506A of the act will be the sole basis
for FDA's regulation of postapproval manufacturing changes for products
approved under NDA's or ANDA's. The guidance provides recommendations
to holders of approved new drug and ANDA's who intend to make
postapproval changes in accordance with section 506A of the act.
Section 506A of the act explicitly provides FDA the authority to use
guidance documents to determine the type of changes that do or do not
have a substantial potential to adversely affect the safety or
effectiveness of the drug product.
OMB has now approved the collection of information and has assigned
OMB control number 0910-0431. This 6-month approval expires on May 31,
2000. By that date, FDA hopes to have completed the normal information
clearance process initiated by this 60-day notice, and the agency hopes
to obtain OMB approval for this collection of information for the usual
3-year period. An agency may not conduct or sponsor, and a person is
not required to respond to, a collection of information unless it
displays a currently valid OMB control number.
Dated: December 29, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-236 Filed 1-5-00; 8:45 am]
BILLING CODE 4160-01-F
