Agency Information Collection Activities; Submission for OMB Review; Comment Request; Dissemination of Information on Unapproved/New Uses for Marketed Drugs, Biologics, and Devices

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 98N-0222]

Agency Information Collection Activities; Submission for OMB

Review; Comment Request; Dissemination of Information on Unapproved/New

Uses for Marketed Drugs, Biologics, and Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

proposed collection of information listed below has been submitted to

the Office of Management and Budget (OMB) for review and clearance

under the Paperwork Reduction Act of 1995 (the PRA).

DATES: Submit written comments on the collection of information by

August 23, 1999.

ADDRESSES: Submit written comments on the collection of information to

the

[[Page 40009]]

Office of Information and Regulatory Affairs, OMB, New Executive Office

Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Wendy

Taylor, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information

Resources Management (HFA-250), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-827-1482.

SUPPLEMENTARY INFORMATION: In compliance with section 3507 of the PRA

(44 U.S.C. 3507), FDA has submitted the following proposed collection

of information to OMB for review and clearance.

Dissemination of Information on Unapproved/New Uses for Marketed

Drugs, Biologics, and Devices (OMB Control No. 0910-0390)--

Extension

In the Federal Register of November 20, 1998 (63 FR 64555), FDA

published a final rule to add a new part 99 (21 CFR part 99) entitled

``Dissemination of Information on Unapproved/New Uses for Marketed

Drugs, Biologics, and Devices.'' The final rule implemented section 401

of the Food and Drug Administration Modernization Act (FDAMA) (Pub. L.

105-115). In brief, section 401 of FDAMA amended the Federal Food,

Drug, and Cosmetic Act (the act) to permit drug, biologic, and device

manufacturers to disseminate certain written information concerning the

safety, effectiveness, or benefits of a use that is not described in

the product's approved labeling to health care practitioners, pharmacy

benefit managers, health insurance issuers, group health plans, and

Federal and State Government agencies, provided that the manufacturer

complies with certain statutory requirements. For example, the

information that is to be disseminated must be about a drug or device

that is being legally marketed; it must be in the form of an unabridged

reprint or copy of a peer-reviewed journal article or reference

publication; and it must not be derived from another manufacturer's

clinical research, unless that other manufacturer has given its

permission for the dissemination. The information must be accompanied

by certain information, including a prominently displayed statement

that the information discusses a use or uses that have not been

approved or cleared by FDA. Additionally, 60 days before dissemination,

the manufacturer must submit to FDA a copy of the information to be

disseminated and any other clinical trial information that the

manufacturer has relating to the safety or effectiveness of the new

use, any reports of clinical experience that pertain to the safety of

the new use, and a summary of such information.

The rule sets forth the criteria and procedures for making such

submissions to FDA. Under the rule, a submission would include a

certification that the manufacturer has completed clinical studies

necessary to submit a supplemental application to FDA for the new use

and will submit the supplemental application within 6 months after its

initial dissemination of information. If the manufacturer has planned,

but not completed, such studies, the submission would include proposed

protocols and a schedule for conducting the studies, as well as a

certification that the manufacturer will complete the clinical studies

and submit a supplemental application no later than 36 months after its

initial dissemination of information. The rule also permits

manufacturers to request extensions of the time period for completing a

study and submitting a supplemental application and to request an

exemption from the requirement to submit a supplemental application.

The rule prescribes the timeframe within which the manufacturer shall

maintain records that would enable it to take corrective action. The

rule requires the manufacturer to submit lists pertaining to the

disseminated articles and reference publications and the categories of

persons (or individuals) receiving the information and to submit a

notice and summary of any additional research or data (and a copy of

the data) relating to the product's safety or effectiveness for the new

use. The rule requires the manufacturer to maintain a copy of the

information, lists, records, and reports for 3 years after it has

ceased dissemination of the information and to make the documents

available to FDA for inspection and copying.

FDA based its estimates of the number of submissions it would

receive and the number of manufacturers who would be subject to part 99

on the number of efficacy and new use supplements for approved drugs,

biologics, and devices received in fiscal year (FY) 1997 and on a

projected increase in supplements due to FDAMA. In FY 1997, FDA

received 198 efficacy and new use supplements from 115 manufacturers.

The number of supplements increased 100 percent from FY 1995 to FY 1997

as a result of two new initiatives, the Prescription Drug User Fee Act

and a new pediatric labeling regulation. If FDAMA results in an

additional 50 percent increase in the number of supplements and a

corresponding increase in the number of manufacturers, then the

estimated number of submissions under part 99 is 297 (198 + (0.5 x

198)), and the estimated number of manufacturers is 172 (115 + (0.5 x

115)). These figures are reflected in Tables 1 and 2 of this document

for Secs. 99.201(a)(1), 99.201(a)(2), 99.201(a)(3), 99.201(b),

99.201(c), 99.501(a)(1), 99.501(a)(2), 99.501(b)(1), 99.501(b)(3), and

99.501(c).

The estimated burden hours for these provisions are provided in the

following paragraphs of this document.

Section 99.201(a)(1) requires the manufacturer to provide an

identical copy of the information to be disseminated, including any

required information. The manufacturer must compile this information to

prepare its submission to FDA. FDA estimates that 40 hours would be

required per submission. Because 297 annual responses are expected

under Sec. 99.201(a)(1), the total burden for this provision is 11,880

hours (297 responses x 40 hours per response).

Section 99.201(a)(2) requires the manufacturer to submit clinical

trial information pertaining to the safety and effectiveness of the new

use, clinical experience reports on the safety of the new use, and a

summary of the information. FDA estimates 24 burden hours per response

for this provision for assembling, reviewing, and submitting the

information and assumes that the manufacturer will have already

acquired some of this information in order to decide whether to

disseminate information on an unapproved use under part 99. The total

burden for this provision is 7,128 hours (297 annual responses x 24

hours per response).

Section 99.201(a)(3) requires the manufacturer to explain its

search strategy when assembling its bibliography. The manufacturer

would have developed and used its search strategy before preparing the

bibliography. FDA estimates that 1 hour would be required for the

explanation. Because 297 annual responses are expected under

Sec. 99.201(a)(3), the total burden for this provision is 297 hours

(297 annual responses x 1 hour per response).

Section 99.201(b) requires the manufacturer's attorney, agent, or

other authorized official to sign its submissions, certifications, and

requests for an exemption. FDA estimates that 30 minutes are necessary

for such signatures. Because 297 annual responses are expected under

Sec. 99.201(b), the total burden for this provision is 148.5 hours (297

response x 0.5 hours per response = 148.5 hours).

Section 99.201(c) requires the manufacturer to provide two copies

with its original submission. FDA does not expect that copying the

submission

[[Page 40010]]

will be time-consuming. FDA estimates the burden to be 30 minutes.

Because 297 annual responses are expected under Sec. 99.201(c), the

total burden for this provision is 148.5 hours.

While the act requires manufacturers to provide a submission to FDA

before they disseminate information on unapproved/new uses, it also

permits manufacturers to: (1) Have completed studies and promise to

submit a supplemental application for the new use within 6 months after

the date of initial dissemination, (2) provide protocols and a schedule

for completing studies and submitting a supplemental application for

the new use within 36 months after the date of initial dissemination,

(3) have completed studies and have submitted a supplemental

application for the new use, or (4) request an exemption from the

requirement to submit a supplemental application. These possible

scenarios are addressed in Secs. 99.201(a)(4)(i)(A),

99.201(a)(4)(ii)(A), 99.201(a)(5), and 99.205(b), respectively.

To determine the number of responses in Secs. 99.201(a)(4)(i)(A),

99.201(a)(4)(ii)(A), 99.201(a)(5), and 99.205(b), FDA began by

estimating the number of requests for an exemption under

Sec. 99.205(b). The legislative history indicates that such exemptions

are to be limited. In the final rule, FDA estimated that approximately

10 percent of all respondents would seek--or 10 percent of all

submissions would contain--an ``economically prohibitive'' exemption

(resulting in 17 total respondents and approximately 30 annual

responses) and that the estimated reporting burden per response would

be 82 hours. This results in a total hour burden of 2,460 hours for

Sec. 99.205(b) (30 submissions x 82 hours per submission).

The estimated increase in the number of exemption requests results

in a corresponding decrease in the remaining number of respondents and

submissions under Secs. 99.201(a)(4)(i)(A), 99.201(a)(4)(ii)(A), and

99.201(a)(5). FDA assumes that the remaining 267 submissions (297 total

submissions--30 submissions containing an exemption request) will be

divided equally among Secs. 99.201(a)(4)(i)(A), 99.201(a)(4)(ii)(A),

and 99.201(a)(5), resulting in 89 responses in each provision (267

submissions/3 provisions). FDA has estimated the number of respondents

in a similar fashion ((172 total respondents--17 respondents submitting

an exemption request)/3 provisions = 51.6, rounded up to 52 respondents

per provision).

As stated earlier, Sec. 99.201(a)(4)(i)(A)) requires the

manufacturer, if the manufacturer has completed studies needed for the

submission of a supplemental application for the new use, to submit the

protocol(s) for the completed studies, or, if the protocol was

submitted to an investigational new drug application (IND) or

investigational device exemption (IDE), to submit the IND or IDE

number(s), the date of submission of the protocol(s), the protocol

number(s), and the date of any amendments to the protocol(s) must be

submitted with the application. This is information that each

manufacturer already maintains for its drugs or devices. FDA estimates

that 30 hours would be required for this response. The total burden for

this provision is 2,670 hours (89 annual responses x 30 hours per

response).

For manufacturers who submit protocols and a schedule for

conducting studies, Sec. 99.201(a)(4)(ii)(A)) requires the manufacturer

to include, in its schedule, the projected dates on which the

manufacturer expects the principal study events to occur. Manufacturers

would have to contact the studies' principal investigator(s) and other

company officials. FDA estimates a manufacturer would need

approximately 60 hours to include the projected dates. The total burden

for this provision is 5,340 hours (89 annual responses x 60 hours per

response).

If the manufacturer has submitted a supplemental application for

the new use, Sec. 99.201(a)(5) requires a cross-reference to that

supplemental application. Manufacturers already maintain this

information. FDA estimates that 1 hour would be needed to comply with

the requirement. The total burden for this provision is 89 hours (89

annual responses x 1 hour per response).

Under Sec. 99.203, a manufacturer who has certified that it will

complete studies necessary to submit a supplemental application within

36 months after its submission to FDA, but later finds that it will be

unable to complete such studies or submit a supplemental application

within that time period, may request an extension of time from FDA.

Such requests for extension should be limited, occurring less than 1

percent of the time, because manufacturers and FDA, when developing or

reviewing study protocols, should be able to identify when a study will

require more than 36 months to complete. Section 99.203 contemplates

extension requests under two different scenarios. Under Sec. 99.203(a),

a manufacturer may make an extension request before it makes a

submission to FDA regarding the dissemination of information under part

99. The agency expects such requests to be limited, occurring less than

1 percent of the time (or 1 annual response), and that such requests

will result in a reporting burden of 10 hours per request. The total

burden hours for this provision, therefore, is 10 hours (1 annual

response x 10 hours per response).

Section 99.203(b) specifies the contents of a request to extend the

time for completing planned studies after the manufacturer has provided

its submission to FDA. The required information includes a description

of the studies, the current status of the studies, reasons why the

study cannot be completed on time, and an estimate of the additional

time needed. FDA estimates that 10 hours for reporting the required

information under Sec. 99.203(b) because it would require consultation

between the manufacturer and key individuals (such as the study's

principal investigator(s)). As in the case of Sec. 99.203(a), the

expected number of responses is very small (1 annual response), and the

total burden hours for this provision is 10 hours (1 annual response x

10 hours per response).

Section 99.203(c) requires two copies of an extension request (in

addition to the request required under section 554(c)(3) of the act (21

U.S.C. 360aaa-3)). FDA estimates that these copies would result in a

reporting burden of 30 minutes. This requirement would apply to

extension requests under Sec. 99.203(a) and (b), so the total number of

annual responses is 2, resulting in a total burden hour for this

provision of 1 hour (2 annual responses x 0.5 hours per response).

Section 99.501(a)(1) requires the manufacturer to maintain records

that identify recipients by category or individually. Under

Sec. 99.301(a)(3), FDA will notify the manufacturer whether it needs to

maintain records identifying individual recipients due to special

safety considerations associated with the new use. This means that, in

most cases, the manufacturer will only have to maintain records

identifying recipients by category. In either event, the manufacturer

will know whether it must maintain records that identify individual

recipients before it begins disseminating information. The time

required to identify recipients individually should be minimal, and the

time required to identify recipients by category should be even less.

FDA estimates the burden for this provision to be 10 hours, and,

because 297 annual responses are expected under Sec. 99.501(a)(1), the

total burden for this provision is 2,970 hours (297 annual responses x

10 hours per response).

[[Page 40011]]

Section 99.501(a)(2) requires the manufacturer to maintain a copy

of the information it disseminates. FDA estimates the burden to be 1

hour. Because 297 annual responses are expected under

Sec. 99.501(a)(2), the total burden for this provision is 297 hours

(297 annual responses x 1 hour per response).

Section 99.501(b)(1) requires the manufacturer to submit to FDA

semiannually a list containing the articles and reference publications

that were disseminated in the preceding 6-month period. FDA tentatively

estimates a burden of 8 hours for this provision. The actual burden may

be less if the manufacturer develops and updates the list while it

disseminates articles and reference publications during the 6-month

period (as opposed to generating a completely new list at the end of

each 6-month period) and if the volume of disseminated materials is

small. The total burden for this provision is 4,752 hours (297

responses submitted semiannually x 8 hours per response = 297 x 2 x 8 =

4,752 hours).

Section 553(a)(2) of the act (21 U.S.C. 360aaa-2) requires

manufacturers that disseminate information to submit to FDA

semiannually a list that identifies the categories of providers who

received the articles and reference publications. Section 99.501(b)(2)

also requires the list to identify which category of recipients

received each particular article or reference publication. If each of

the 297 submissions under part 99 results in disseminated information,

Sec. 99.501(b)(2) would result in 594 lists (297 submissions x 2

submissions per year) identifying which category of recipients received

each particular article or reference publication. The agency estimates

the burden to be only 1 hour per response because this type of

information is maintained as a usual and customary business practice,

and the total burden for this provision is 594 hours (594 lists x 1

hour per list).

In relation to Sec. 99.201(a)(2), Sec. 99.501(b)(3) requires the

manufacturer to provide, on a semiannual basis, a notice and summary of

any additional clinical research or other data relating to the safety

and effectiveness of the new use and, if it possesses such research or

data, to provide a copy to FDA. This burden should not be as extensive

as that in Sec. 99.201(a)(2). FDA estimates the burden to be 20 hours

per response, for a total burden of 11,880 hours for this provision

(297 annual responses submitted semiannually x 20 hours per response =

297 x 2 x 20 = 11,880 hours).

If a manufacturer discontinues or terminates a study before

completing it, Sec. 99.501(b)(4)) requires the manufacturer to state

the reasons for discontinuing or terminating the study in its next

progress report. Based on FDA's regulatory experience in monitoring

studies to support supplemental applications, FDA estimates this would

affect only 1 percent of all applications (297 at 0.01 = 2.97, rounded

up to 3) and only 2 manufacturers (172 x 0.01 = 1.72, rounded up to 2).

FDA estimates 2 hours of reporting time for this requirement because

the manufacturer should know the reasons for discontinuing or

terminating the study and would only need to provide those reasons in

its progress report. The total burden hours for this provision is 6

hours (3 annual responses x 2 hours per response).

Section 99.501(b)(5) requires the manufacturer to submit any new or

additional information that relates to whether the manufacturer

continues to meet the requirements for the exemption after an exemption

has been granted. FDA cannot determine, at this time, how many

exemption requests will be granted, but, for purposes of this

information of collection, has estimated that 10 percent of all

submissions will contain an exemption request (297 total submissions x

0.10 = 29.7, rounded up to 30) and has assumed that all exemption

requests will be granted, for a total of 30 annual responses. The

information sought under Sec. 99.501(b)(5) pertains solely to new or

additional information and is not expected to be as extensive as the

information required to obtain an exemption. Thus, FDA tentatively

estimates the burden for Sec. 99.501(b)(5) to be 41 hours per response

(or half the burden associated with an exemption request), for a total

burden of 1,230 hours for this provision (30 annual responses x 41

hours per response).

Section 99.501(c) requires the manufacturer to maintain records for

3 years after it has ceased dissemination of the information. FDA

estimates the burden hour for this provision to be 1 hour. Because 297

annual responses are expected under Sec. 99.501(c), the total burden

for this provision is 297 hours.

Description of Respondents: All manufacturers (persons and

businesses, including small businesses) of drugs, biologics, and device

products.

In the Federal Register of March 4, 1999 (64 FR 10470), the agency

requested comments on the proposed collections of information. No

comments were received.

FDA estimates the burden of this collection of information as

follows:

Table 1.--Estimated Annual Reporting Burden\1\

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Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Respondents Response Responses Response

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99.201(a)(1) 172 1.7 297 40 11,880

99.201(a)(2) 172 1.7 297 24 7,128

99.201(a)(3) 172 1.7 297 1 297

99.201(a)(4)(i)(A) 52 1.7 89 30 2,670

99.201(a)(4)(ii)(A) 52 1.7 89 60 5,340

99.201(a)(5) 52 1.7 89 1 89

99.201(b) 172 1.7 297 0.5 148.5

99.201(c) 172 1.7 297 0.5 148.5

99.203(a) 1 1 1 10 10

99.203(b) 1 1 1 10 10

99.203(c) 2 1 2 0.5 1

99.205(b) 17 1.8 30 82 2,460

99.501(b)(1) 172 3.4 594 8 4,752

99.501(b)(2) 172 3.4 594 1 594

99.501(b)(3) 172 3.4 594 20 11,880

99.501(b)(4) 2 1.7 3 2 6

99.501(b)(5) 17 1.8 30 41 1,230

[[Page 40012]]

Total Hours 48,644

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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information

Table 2.--Estimated Annual Recordkeeping Burden\2\

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Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Recordkeepers Recordkeeping Records Recordkeeper

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99.501(a)(1) 172 1.7 297 10 2,970

99.501(a)(2) 172 1.7 297 1 297

99.501(c) 172 1.7 297 1 297

Total Hours 3,564

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\2\ There are no capital costs or operating and maintenance costs associated with this collection of

information.

The estimated burden associated with the information collection

requirements for this rule is 52,208 hours.

Dated: July 15, 1999.

Margaret M. Dotzel,

Acting Associate Commissioner for Policy.

[FR Doc. 99-18767 Filed 7-22-99; 8:45 am]

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