Agency Information Collection Activities: Proposed Collection; Comment Request

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

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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.

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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]

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