**Docket No. 00N-1674**

**0910-0370**

**SPECIFIC REQUIREMENTS ON CONTENT AND FORMAT OF LABELING FOR HUMAN
PRESCRIPTION DRUGS;**

**ADDITION OF \"GERIATRIC USE\" SUBSECTION IN THE LABELING**

A. [Justification]{.underline}

1\. [Circumstances of Information Collection]{.underline}

OMB approval under the Paperwork Reduction Act (44 U.S.C. 35) is
requested for the information requirements contained in the Food and
Drug Administration (FDA) Specific Requirements on Content and Format of
Labeling for Human Prescription Drugs; Addition of \"Geriatric Use\"
Subsection in the Labeling (Geriatric Labeling) (21 CFR Part 201). These
regulations are issued under the authority of sections 201, 310, 501,
503, 505, 508, 510, 512, 530-542, 701, 704, 721 of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 358,
360, 360b, 360gg-360ss, 371, 374, 379e); and sections 215, 301, 351, 361
of the Public Health Service Act (42 U.S.C. 216, 241, 262, 264). The
regulations are necessary to facilitate the safe and effective use of
prescription drugs in older populations.

Section 201.57(f)(10) (21 CFR 201.57(f)(10)) requires that the
\"Precautions\" section of prescription drug labeling must include a
subsection on the use of the drug in elderly or geriatric patients (aged
65 and over). The information collection burden imposed by this
regulation consists of designing, testing, and submitting the geriatric
use subsection of the labeling.

FDA is requesting OMB approval for the following information collection
requirement in the regulations establishing a geriatric labeling
subsection (21 CFR 201.57(f)(10):

§ 201.57(f)(10) (reporting) Establishes a Geriatric Labeling subsection
prescription drug labeling

2\. [Purpose and Use of Information]{.underline}

The regulation is necessary to facilitate the safe and effective use of
prescription drugs in older populations. The geriatric use subsection
enables physicians to more effectively access geriatric information in
physician prescription drug labeling.

3\. [Use of Improved Information Technology]{.underline}

[Electronic Regulatory Submissions for Archive]{.underline}. The Food
and Drug Administration Modernization Act of 1997 (FDAMA) and the
Prescription Drug User Fee Act (PDUFA) II reauthorization mandate that
the agency develop and update its information management infrastructure
to allow, by fiscal year 2002, the paperless receipt and processing of
investigational new drug applications and new drug applications, as
defined in PDUFA, and related submissions. Moving an
information-intensive activity, such as drug regulatory review, from a
paper-based to an electronic environment will provide a number of
benefits. This is true simply from the perspective of generating,
handling, and storing the huge volumes of paper commonly associated with
applications. In general, these paper applications (often containing
hundreds of volumes) are submitted with several copies, a process that
can take several days longer than preparation of a corresponding
electronic submission, which the agency can easily reproduce.
Preparation of applications in electronic format results in direct cost
savings related to materials, supplies, and paper handling logistics
(i.e., labor, facilities). However, this is expected to be only a small
portion of the potential savings. The most substantial burden reduction
may not be in information recording, reporting, and record-keeping, but
in the flexibility, efficiency, speed, and ease of filing required
information that will result in cost savings to regulated industry, as
well as FDA.

In September 1997, FDA published the Guidance for Industry on "Archiving
Submissions in Electronic Format --- NDAs". This guidance provided for
the receipt and archive of electronic Case Report Forms (CRF) and Case
Report Tabulations (CRT) without an accompanying paper copy. In FY 1998,
FDA established an Electronic Document Room (EDR) to manage the receipt
and handling of all electronic submissions. In January 1999, FDA
published the Guidance for Industry on "Providing Regulatory Submissions
in Electronic Format --- NDAs". This guidance document covers the full
NDA and is not limited to CRTs and CRFs.

FDA has received 264 NDAs with electronic components since January 1999.
Of these 89 were new submissions. In the same period the agency has also
received 273 supplements with electronic components of which 170 were
new supplements. As of the end of August 2000, the agency\'s EDR was
comprised of three groups of NDAs: those that consisted of items 11
and/or 12 only (109 or 42.4%); those that consisted of various items
with or without items 11 and 12 (105 or 40.9%); and those consisting of
nearly all 19 possible NDA data items (43 or 16.7%). A total of 197
(76.7%) of NDAs with electronic components had items 11 and/or 12
submitted in an electronic format.

[Secure E-Mail]{.underline}. During a drug's development cycle,
communications between agency review divisions and the company
developing the drug is sensitive and proprietary. Prior to using secure
E-mail, agency methods of "secure" communication included U.S. mail,
courier, telephone, and facsimile. These methods, some of which are not
entirely secure, can be inefficient or time consuming, and can
significantly contribute to the overall length of time involved in the
drug review process. The widespread use of E-mail across the Internet
offers a more efficient and scaleable means of information exchange.
However, security risks of communicating over the Internet are well
known. The information technology industry is answering security
concerns by developing new standards of cryptographic techniques, E-mail
formats, authentication algorithms, and other related aspects of secure
communications. In 1998, the agency conducted a formal requirements
study for secure E-mail which led to the selection of Worldtalk
Corporation's WorldSecure Server as the base pilot platform. The agency
completed a pilot, the final system design and implemented the
production system in October 1999. The system is used across the Center
for Drug Evaluation and Research to communicate with over 15 companies
and more than 150 individuals in those companies. The system also
provides virus scanning and extensive E-mail filtering capabilities.

[ICH M2]{.underline}. The International Conference on Harmonisation
(ICH) of Technical Requirements for the Registration of Pharmaceuticals
for Human Use was formed to minimize waste in the discovery,
development, regulation, manufacture, marketing, and use of human
therapeutic products worldwide. The regulatory authorities of Europe,
Japan, and the United States joined with their respective pharmaceutical
trade associations in an agreement to take action on harmonization by
participating in the ICH.

The ICH Multi-disciplinary Group 2 (M2) Expert Working Group (EWG) was
established to determine electronic standards and provide solutions to
facilitate international electronic communication in the three ICR
regions. The first effort of the M2 EWG was to establish a series of
recommendations that would form the basis for standardized electronic
communication in each of the three regions. These recommendations
included physical media formats, secure communications, and structured
data formats. Building on these standards, the EWG completed a detailed
specification for the secure, electronic transmission of individual case
safety reports (adverse event reports). The specification is being used
to format and transmit electronic adverse event reports directly from a
company's database to the FDA Adverse Event Reporting System (AERS).

The production of a specification for an electronic common technical
document (CTD) was the next major effort assigned to the M2 EWG. The ICH
Steering committee agreed in March 1999 that this effort should be
undertaken by the M2 EWG in cooperation with the subject matter expert
working groups for each section of the CTD. The CTD working groups are
charged with harmonizing the format and content of the application
documents for new product applications. The resulting ICH guidances,
when implemented, will change the content and format of NDA submissions
to the FDA. The M2 EWG is working with the CTD Step 2 documents to
define the functionality to be included in the electronic submission for
CTD submissions.

4\. [Efforts to Identify Duplication]{.underline}

The information required for geriatric labeling is not available from
any other source except the manufacturer. No other government agency
collects these data.

5\. [Involvement of Small Entities]{.underline}

The affected pharmaceutical companies can be classified into three
industry sectors: Large innovator firms (more than 750 employees), small
innovator firms (fewer than 750 employees), and independent generic
firms (fewer than 750 employees). Within the two innovator sectors,
almost all the costs will be borne by the large innovators because large
firms sponsor almost all innovator product applications. Although the
occasional product sponsored by a small innovator firm may require
additional research and analysis to support geriatric labeling, it is
unlikely that any one firm would have more than one or two such products
or that any one of these products would be marketed if it could not
generate over several hundred thousand dollars in revenue per year. In
addition, firms had up to 6 years to comply with the regulation for all
products; the estimated one-time cost per product would be extremely low
relative to the income generated from such product(s) during this
period. FDA therefore concluded that this regulation will not have a
significant effect on a substantial number of small entities.

It is also important to note that FDA must ensure that regulated
products from all manufacturers (large and small) are safe and
effective. It is not possible to provide exemptions or reduce
prescription drug labeling requirements for small businesses without
seriously compromising information important to the safe and effective
use of prescription drugs.

6\. [Consequences if Information Collected Less Frequently]{.underline}

FDA would be unable to ensure that new drug products with clinically
significant use in a geriatric population carry adequate labeling for
use in that subpopulation.

7\. [Consistency with Guidelines in 5 CFR 1320.6]{.underline}

Special circumstances that would cause an information collection to be
conducted in a manner:

a\) Requiring respondents to report information to the agency more often
than quarterly - Any public health emergency as, for example, a
situation in which a drug product might pose a threat to the lives of
those using it, could require the agency to immediately solicit
information directly related to the emergency.

b\) Requiring respondents to prepare a written response to a collection
of information in fewer than 30 days after receipt of it - No
requirement in 21 CFR 201.57(f)(10).

c\) Requiring respondents to submit more than an original and two copies
of any document - No requirement in 21 CFR 201.57(f)(10).

d\) Requiring respondents to maintain records, other than health,
medical, government contract, grant-in-aid, or tax records for more than
three years - Drug product manufacturers are required to retain records
specifically associated with a drug product for at least 1 year after
the expiration date. Depending on the approved dating period, it is
possible that records would be retained for more than 3 years.
Availability of these records provide an opportunity to followup on
complaints and adverse reports received during a drug\'s marketing
period. Failure to have these records available for an investigation
could prevent the resolution of undesirable and potentially
life-threatening conditions.

d\) In connection with a statistical survey, that is not designed to
produce valid and reliable results that can be generalized to the
universe of study - No requirement in 21 CFR 201.57(f)(10).

e\) Requiring the use of a statistical data collection that has not been
reviewed and approved by OMB - No requirement in 21 CFR 201.57(f)(10).

f\) That includes a pledge of confidentiality that is not supported by
authority established in a statute or regulation, that is not supported
by disclosure and data security policies that are consistent with the
pledge, or which unnecessarily impedes sharing of data with other
agencies for compatible confidential use - No requirement in 21 CFR
201.57(f)(10).

g\) Requiring respondents to submit proprietary trade secret, or other
confidential information unless the agency can demonstrate that it has
instituted procedures to protect the information\'s confidentiality to
the extent permitted by law - FDA regularly deals with proprietary
information and has procedures in place to protect the information\'s
confidentiality.

8\. [Consultations Outside the Agency]{.underline}

In the Federal Register of January 5, 2001, (66 FR 1142), the agency
requested comments on the proposed collections of information. No
significant comments were received.

In the Federal Register of November 1, 1990 (55 FR 46134), FDA proposed
amending its drug labeling regulations to establish a geriatric
subsection in the \"Precautions\" section of the labeling. The Agency
received approximately 60 comments on the proposed rule. These comments
represented many interests\--Congress; individual consumers; nonprofit
institutions or associations; physicians; professional societies;
organizations with special interests in the elderly; drug manufacturers;
and others. In the August 27, 1997 final rule (62 FR 45313) FDA
responded in detail to these comments.

9\. [Remuneration of Respondents]{.underline}

No payment or gift was provided to respondents.

10\. [Assurance of Confidentiality]{.underline}

Certain data and information involved in a labeling supplement may be
confidential. Confidentiality is maintained over trade secret or
confidential, commercial or financial information under 21 CFR 20.61 and
investigatory records under 21 CFR 20.64. In addition, certain
subparagraphs of 21 CFR 314.430 and 514.11 provide confidentiality of
information contained in NDAs, ANDAs, and NADAs.

11\. [Questions of a Sensitive Nature]{.underline}

There are no questions of a sensitive nature.

12\. [Estimates of Annualized Hour Burden]{.underline}

The information collection requirements of the Geriatric labeling
regulations can be charted as follows:

+-------------------+--------+----------+---------+---------+--------+
| Estimated Annual  |        |          |         |         |        |
| Reporting Burden  |        |          |         |         |        |
+===================+========+==========+=========+=========+========+
| 21 CFR Section    | Number | Number   | Total   | Hours   | Total  |
|                   | of     | of       | Annual  | Per     | Hours  |
|                   | R      | R        | Re      | R       |        |
|                   | espon- | esponses | sponses | esponse |        |
|                   |        | Per      |         |         |        |
|                   | dents  | Re       |         |         |        |
|                   |        | spondent |         |         |        |
+-------------------+--------+----------+---------+---------+--------+

+-------------------+--------+----------+---------+---------+--------+
| 201.57(f)(10)     | 83     | 1.49     | 124     | 8       | 992    |
| NDAs              |        |          |         |         |        |
|                   | 117    | 3.96     | 464     | 2       | 928    |
| 201.57(f)(10)     |        |          |         |         |        |
| ANDAs             |        |          |         |         | 1,920  |
|                   |        |          |         |         |        |
| TOTAL             |        |          |         |         |        |
+-------------------+--------+----------+---------+---------+--------+

13\. [Estimates of Annualized Cost Burden to Respondents]{.underline}

The cost of this provision includes the time needed for reviewing
instructions, gathering and maintaining the data needed, and designing
and manufacturing new labeling that includes a geriatric use subsection
in the \"Precautions\" section of the labeling. The estimate is based on
the following wage rates: Upper management at \$70.00 per hour; middle
management at \$35.00 per hour; and clerical assistance at \$23.00 per
hour. Using an averaged wage rate of \$50.00 per hour (based on the
percentage of time required for each type of employee), the total cost
burden to respondents would be \$ 96,000.

14\. [Estimates of Annualized Cost Burden to the Government]{.underline}

The cost to FDA of reviewing revised labeling including the geriatric
subsection will vary considerably for already approved drug products,
depending on whether the drug is a priority drug, and which of the
labeling options in § 201.57(f)(10) is appropriate for the product. For
drug products approved after the effective date of the rule, approval of
a geriatric labeling subsection will be part of the NDA approval
process.

The agency estimates it takes reviewers approximately 5 hours to review
the revised geriatric labeling subsection for the 124 innovator products
and 1 hour for the 464 generic products. Based on an average hourly cost
of \$55.00 per hour for this level of reviewer (including overhead
expenses and support), the total cost to FDA would be \$59,620 (124
submissions x 5 hours x \$55.00 = \$34,100); (464 x 1 hour x \$55.00 =
\$25,520).

15\. [Changes in Burden]{.underline}

There is a 32,880 burden hour decrease in this collection renewal
because the previous estimate calculated labeling changes for products
marketed at the time the final rule became effective. This estimate
calculates geriatric labeling only for new NDAs and ANDAs received
annually.

16\. [Time Schedule, Publication, and Analysis Plans]{.underline}

FDA does not intend to publish the results of the information collection
requirements that would be imposed by these regulations.

17\. [Displaying of OMB Expiration Date]{.underline}

There are no forms associated with this collection.

18\. [Exceptions to Certification Statement - Item 19]{.underline}

There are no exceptions to the \"Certification for Paperwork Reduction
Act Submissions\" for this proposal.

prageri.ss 3/13/01