[Federal Register Volume 69, Number 78 (Thursday, April 22, 2004)]
[Proposed Rules]
[Pages 21778-21796]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-9069]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 201, 208, and 209
[Docket No. 2003N-0324]
RIN 0910-AC35
Toll-Free Number for Reporting Adverse Events on Labeling for
Human Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations governing the format and content of labeling for human
drug products for which an application is approved under section 505 of
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355). The
proposed rule would require the addition of a statement that includes a
toll-free number and advises that the number is to be used only for
reporting side effects and is not intended for medical advice (the side
effects statement). When finalized, this rule will bring FDA
regulations into compliance with provisions of the Best Pharmaceuticals
for Children Act (the BPCA).
DATES: Submit written or electronic comments by July 21, 2004. See
section IV of this document for the proposed effective date of any
final rule based on this proposal.
ADDRESSES: You may submit comments, identified by Docket No. 2003N-0324
and RIN 0910-AC35, by any of the following methods:
Federal eRulemaking Portal: http://www.regulations.gov. Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments. Follow the instructions for submitting comments on the
agency Web site.
E-mail: [email protected]. Include Docket
No. 2003N-0324 and RIN 0910-AC35 in the subject line of your e-mail
message.
[[Page 21779]]
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or
CD-ROM submissions]: Division of Dockets Management, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the agency name and
Docket No. 2003N-0324 and RIN 0910-AC35 or Regulatory Information
Number (RIN) for this rulemaking. All comments received will be posted
without change to http://www.fda.gov/dockets/ecomments, including any
personal information provided. For detailed instructions on submitting
comments and additional information on the rulemaking process, see the
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.fda.gov/dockets/ecomments and/or
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Carol Drew, Center for Drug Evaluation
and Research (HFD-7), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857, 301-594-2041.
SUPPLEMENTARY INFORMATION:
I. Background
A. BPCA Requirements
Section 17 of the BPCA (Public Law 107-109) requires FDA to issue a
final rule requiring the labeling of each human drug product for which
an application is approved under section 505 of the act (21 U.S.C. 355)
to include: (1) A toll-free number maintained by FDA for the purpose of
receiving reports of adverse events regarding drugs, and (2) a
statement that the number is to be used for reporting purposes only,
not to seek or obtain medical advice. The BPCA states that the final
rule must implement the labeling requirement so as to reach the
broadest consumer audience and minimize the cost to the pharmacy
profession.
B. MedWatch
FDA already has an adverse drug events reporting program. FDA's
existing MedWatch safety information and adverse event reporting
program (MedWatch program) includes a toll-free number to facilitate
the reporting of adverse events directly to the agency by both health
care practitioners and consumers.
Under the existing MedWatch program, consumers and health care
practitioners may report serious adverse events, side effects, or
problems they suspect are associated with drug products they use or
prescribe. To obtain accurate and complete reports of side effects with
a potential association to drug products, FDA generally recommends that
consumers advise their health care practitioners to report side effects
to the drug manufacturer or MedWatch program. However, consumers may
also report side effects to FDA directly. A postage-paid MedWatch 3500
form will be mailed or faxed to a consumer who calls 1-800-FDA-1088 and
requests a form. A completed form can be mailed or submitted to
MedWatch's fax number, 1-800-FDA-0178. Reporting also may be done
online at http://www.fda.gov/medwatch. FDA encourages consumers to use
the MedWatch Website to report adverse events. Consumers who call the
MedWatch phone number are given the MedWatch Website address and the
option of completing and submitting the reporting form on the Internet.
Currently consumers receive an acknowledgement from FDA after their
report is received. Consumers are personally contacted only if
additional critically important information is needed. All reports are
entered into a database and are evaluated by a safety evaluator. All
information is submitted in confidence and protected to the fullest
extent of the law.
C. Existing Labeling Requirements
Section 505 of the act describes requirements for the agency's
approval of new drug applications (NDAs) and abbreviated new drug
applications (ANDAs). FDA regulates many forms of drug labeling for
drug products approved under section 505 of the act. Regulated labeling
includes: A prescription drug product's approved labeling directed to
health care practitioners (physician labeling), FDA-approved Medication
Guides, patient package inserts (PPIs) for certain drug products, and
over-the-counter (OTC) drug product labeling.
II. Description of the Proposed Rule
A. FDA's Approach to the BPCA Requirements
FDA is proposing that the MedWatch system should be used to fulfill
the requirements of the BPCA for providing a toll-free number for the
purpose of receiving adverse event reports regarding drug products.
FDA is proposing that the side effects statement be distributed
with each prescription drug product, both new prescriptions and
refills, approved under section 505 of the act and dispensed to
consumers by pharmacies and authorized dispensers in an outpatient
setting. FDA is proposing a number of options/alternatives to meet this
proposed requirement. FDA also is proposing to require the side effects
statement in two categories of drug product labeling: (1) FDA-approved
Medication Guides for drugs approved under section 505 of the act, and
(2) the labeling for OTC drug products approved under section 505 of
the act. Manufacturers may include the side effects statement in PPIs
or Medication Guides on a voluntary basis for products not approved
under section 505 of the act. In addition, FDA has proposed adding
FDA's toll-free MedWatch telephone number to physician labeling in the
proposed rule entitled ``Requirements on Content and Format of Labeling
for Human Prescription Drugs and Biologics; Requirements for
Prescription Drug Product Labels'' (65 FR 81082, December 22, 2000).
FDA believes that this approach will be most likely to reach the
broadest consumer audience and minimize the cost to the pharmacy
profession.
B. Labeling Not Covered Under this Proposed Rule
1. Physician Labeling
FDA is not proposing to modify the requirements for physician
labeling at this time. Although consumers have access to physician
labeling as reprinted in the Physician Desk Reference (PDR), physician
labeling is not written for the consumer audience. In the Federal
Register of December 22, 2000, the agency issued a proposed rule to
revise the physician labeling requirements in 21 CFR 201.56 and 201.57
(the physician labeling rule). The proposed changes to the labeling
format included the addition of adverse drug reaction reporting contact
information for health care practitioners, including FDA's toll-free
MedWatch telephone number. Because physician labeling is directed to
health care practitioners, and FDA anticipates that this labeling will
be updated with the toll-free MedWatch number, the agency is not
proposing modifications to physician labeling at this time. However,
FDA is soliciting comments on this issue.
2. PPIs
PPIs are required by FDA for certain drug products, including oral
contraceptives and estrogen drug products (Sec. Sec. 310.501 and
310.515 (21 CFR 310.501 and 310.515)). Some manufacturers also
voluntarily produce PPIs for drug products. PPIs are an extension of
physician labeling and are often distributed to consumers when the
[[Page 21780]]
drug product is dispensed. FDA is not proposing to require the side
effects statement in PPIs at this time because the proposed requirement
in this rule that pharmacies distribute the side effects statement will
ensure that a broad consumer audience receives it. FDA believes that
requiring changes to PPIs in addition is unnecessary; however, FDA is
soliciting comments on this issue. Manufacturers may provide the side
effects statement voluntarily in PPIs.
C. Benefits of the Proposed Rule to Public Health
FDA has determined that this proposed rule will promote the
agency's mission to protect the public health by informing consumers of
FDA's adverse event reporting program under MedWatch. Data reported as
a result of this proposed rule will supplement data currently reported
and assist the agency in identifying trends in reported adverse events
for specific drug products. These data may result in a review of the
safety and/or effectiveness of particular drug products on the market.
Once an adverse event or product problem is identified, the agency can
initiate various actions to address the problem, such as labeling
changes (e.g., boxed warnings), medical or safety alerts to health care
practitioners, and product withdrawals. For further discussion of the
benefits of this proposed rule, see the agency's analysis of economic
impacts in section V.C of this document.
D. Specific Proposed Changes to the Regulations
1. Side Effects Statement
Section 17 of the BPCA requires that the labeling for each drug
approved under section 505 of the act include: (1) A toll-free number
maintained by FDA for the purpose of receiving reports of adverse
events regarding drug products, and (2) a statement that the number is
to be used for reporting purposes only, not to seek medical advice. FDA
has considered these requirements and has developed a conforming
statement: ``Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.'' FDA believes
this statement comports with the mandate in the BPCA and is brief
enough to convey the appropriate message and fit on the labeling of
drug products. However, FDA is soliciting comments on the wording of
the proposed statements. As stated previously in this document, FDA is
using the established MedWatch toll-free number for consumer reporting.
For OTC products, the side effects statement has been modified to
correspond to the specific requirements for OTC drug product labeling.
FDA consulted with an agency communications specialist in developing
the side effects statement.
FDA is proposing that the side effects statement first direct
consumers to call their doctor for medical advice. FDA is concerned
that consumers may misinterpret a statement to report side effects and
call the agency at the time they or members of their family experience
a side effect, rather than calling their own doctor for immediate, and
possibly critical, medical advice. To make it clear that consumers
experiencing side effects and in need of medical advice should call
their doctor first, FDA has included the first sentence instructing
consumers to call their doctor for medical advice.
FDA is proposing to use the term ``side effects'' rather than
``adverse events'' because of concern that some consumers may not
understand the meaning of the term ``adverse event.'' FDA believes the
term ``side effects'' will be understood by a broader consumer audience
than would the term ``adverse event.''
The current MedWatch program distinguishes serious adverse events,
defined in 21 CFR 314.80, as those where the patient outcome is: death,
life threatening (real risk of dying), hospitalization (initial or
prolonged), disability (significant, persistent or permanent),
congenital anomaly, or required intervention to prevent permanent
impairment or damage. The BPCA does not qualify the type of adverse
event reported to the toll-free number. Therefore, FDA is not proposing
that consumers report only serious adverse events to the MedWatch
program. This is likely to result in more reports to FDA than under the
existing system. The agency solicits comments on whether the term
``side effects'' should be further qualified.
2. Medication Guides
FDA-approved Medication Guides are required for prescription drug
products that the agency has determined pose a serious and significant
public health concern. Because these products have increased risks, FDA
believes that the side effects statement should be included in
Medication Guides required for drug products approved under section 505
of the act.
Part 208 (21 CFR part 208) sets forth the requirements for this
type of patient labeling. Medication Guides provide information when
FDA determines that the information is necessary to patients' safe and
effective use of drug products. Medication Guides have been approved
for approximately 18 prescription drug products, only some of which are
approved under section 505 of the act. Some biological products have
Medication Guides, but those products are not approved under section
505 of the act, and therefore are not covered by these BPCA provisions.
These provisions would apply, however, to any biological products
approved under section 505 that carry Medication Guides.
FDA is proposing that manufacturers be required to include the side
effects statement under the heading, ``What are the possible or
reasonably likely side effects of (name of drug)?''. Manufacturers who
ship drug products for which a Medication Guide is required are
responsible for ensuring that the Medication Guide is available for
distribution to patients by providing sufficient numbers of Medication
Guides to authorized dispensers of drug products. Consumers who receive
the appropriate Medication Guide with their dispensed prescription drug
product will be made aware of FDA's toll-free number to report side
effects by reading the appropriate section of the Medication Guide.
Under Sec. 208.20(a)(4), the letter height or type size for
Medication Guides must be no smaller than 10 points (1 point = 0.0138
inches). FDA is not proposing to modify this requirement; therefore,
the side effects statement in Medication Guides will appear in no
smaller than 10-point letter height or type size.
While FDA is not requiring manufacturers to add the side effects
statement to Medication Guides for those drug products not approved
under section 505 of the act, manufacturers may do so voluntarily.
3. OTC Labeling
Because certain OTC drug products are approved under section 505 of
the act, FDA is proposing that the labeling of those products approved
under NDAs or ANDAs must also contain the side effects statement as
mandated by the BPCA. FDA estimates that there are approximately 350
OTC products approved under an NDA and 172 approved under an ANDA.
In 1999, FDA published a final rule on the labeling of OTC drug
products. The final rule was intended to assist consumers in reading
and understanding OTC drug product labeling and introduced a new format
(drug facts format). In this proposed rule, FDA has modified the side
effects statement for OTC products to correspond to the drug facts
format. Section 201.66 (21 CFR 201.66) addresses format and content
[[Page 21781]]
requirements for OTC drug product labeling. Section 201.66(c) lists the
content requirements for OTC drug product labeling, and Sec. 201.66(d)
specifies the format requirements for OTC drug product labeling,
including the letter height and type size.
The format and content labeling requirements for OTC drug products
in Sec. 201.66 include specific subheadings for presenting
``warnings'' information. The subheading in Sec. 201.66(c)(5)(vii) is
``Stop use and ask a doctor if''. The agency considers this language
similar to the language in the first sentence of the side effects
statement for prescription drug products that advises patients to
``Call your doctor for medical advice about side effects.''
Accordingly, for OTC drug products, the agency is proposing to use the
existing subheading in Sec. 201.66(c)(5)(vii) and include after it the
bulleted statement ``side effects occur.'' The second sentence would
remain the same as for prescription products: ``You may report side
effects to FDA at 1-800-FDA-1088.'' This approach incorporates the side
effects statement in OTC product labeling in the appropriate location,
using existing consumer-friendly language and a minimal amount of
additional labeling space.
The letter height or type size for subheadings and all other
information described in Sec. Sec. 201.66(c)(2) through (c)(9) in OTC
labeling is no smaller than 6-point letter height or type size (Sec.
201.66(d)(2)). Therefore, the OTC side effects statement would appear
in a minimum 6-point letter height or type size. Consistent with Sec.
201.66(c)(9), the telephone number would appear in a minimum 6-point
bold letter height or type size. This requirement is repeated in the
revisions to Sec. 201.66(c)(5)(vii).
4. Pharmacy Provisions
FDA is proposing to add new part 209 (21 CFR part 209) to the
regulations to require pharmacies and authorized dispensers to
distribute the side effects statement to consumers with each
prescription drug product approved under section 505 of the act. Under
this part, the term ``pharmacies'' includes, but is not limited to,
retail, mail-order, hospital, university, or clinic pharmacies, as well
as public health agencies that dispense prescription drugs. The term
``authorized dispenser'' means an individual licensed, registered, or
otherwise permitted by the jurisdiction in which the individual
practices to provide drug products on prescription in the course of
professional practice. The term includes health care practitioners who
dispense prescription drug products from their offices, but does not
include the dispensing of drug samples. FDA does not intend that part
209 apply to health care practitioners administering medication to
inpatients in a hospital or health care facility under an order of a
licensed practitioner, or as part of supervised home health care. FDA
believes that patients receiving drugs under these circumstances will
rely on their health care practitioners to monitor and report adverse
events.
While section 17 of the BPCA requires FDA to reach the broadest
consumer audience, it also requires FDA to minimize costs to the
pharmacy profession. To minimize the cost of the requirement for
pharmacists to distribute the side effects statement, FDA is proposing
to provide a range of options from which pharmacists may choose. These
options are included in proposed Sec. 209.11(b). FDA invites comments
on other options pharmacies might use to distribute the side effects
statement.
Proposed Sec. 209.11(b) provides that pharmacies and authorized
dispensers may choose one of the following methods, or any combination
of the following methods, to distribute the side effects statement to
consumers: (1) Attach a standard-size sticker (1 1/2 by 7/16 inches)
containing the side effects statement to the vial, package, or
container of the prescription drug product; (2) use a pharmacy
prescription vial cap preprinted with the side effects statement; (3)
distribute a separate sheet of paper containing the side effects
statement; (4) distribute consumer medication information such as that
provided by pharmacy software and third party data processing vendors
that contains the side effects statement; or (5) distribute the
appropriate FDA-approved Medication Guide that contains the side
effects statement.
a. Option 1--sticker. The first option for distribution of the side
effects statement by pharmacies and authorized dispensers is to attach
a standard-size pharmacy sticker to the unit package, vial, or
container of the prescription drug product dispensed to the consumer.
FDA is proposing that the letter height or type size of the side
effects statement on any sticker attached to the unit package, vial, or
container of a prescription drug product be no smaller than 6 points.
The side effects statement should be printed in any single, clear,
easy-to-read type style. To minimize the cost of this option for
pharmacies, FDA has determined that the proposed side effects statement
will fit on a standard-size (1 1/2- by 7/16-inch) pharmacy sticker.
FDA recognizes there may be reasons that the sticker option is not
practicable for some drug products, e.g., the packaging of the drug
product is too small to accommodate a sticker, or there are stickers
already necessary that preclude adding another. FDA is not proposing to
require this option. Therefore, a pharmacy or authorized dispenser may
choose any other option.
b. Option 2--preprinted vial cap. The second option for
distribution of the side effects statement by pharmacies and authorized
dispensers is to use a pharmacy prescription vial cap preprinted with
the side effects statement. As with the sticker option, FDA is
proposing that the letter height or type size of the side effects
statement be no smaller than 6 points. The side effects statement
should be printed on the vial cap in any single, clear, easy-to-read
type style. Use of a preprinted vial cap should be useful when the
necessary number of stickers on a prescription vial precludes the
addition of another sticker.
c. Option 3--separate sheet of paper. The third possible method of
distribution is to provide a separate sheet of paper with the side
effects statement to consumers. FDA is proposing that the letter height
or type size of the side effects statement be no smaller than 10 points
to ensure readability. The side effects statement should be in a
single, clear, easy-to-read type style. FDA is not proposing any
further requirements on how this information is presented. The agency
believes that this flexibility will allow pharmacies and authorized
dispensers who choose this option to use existing systems to meet this
requirement.
d. Option 4--consumer medication information. Some pharmacies
voluntarily distribute written information about prescription drug
products to consumers as part of patient medication counseling
activities (consumer medication information). This information is often
attached to or placed in the bag into which the pharmacist puts the
prescription drug product prior to providing it to the consumer.
Consumer medication information is often produced by third party data
processing vendors. Therefore, FDA is providing pharmacies and
authorized dispensers with the option of complying with this regulation
by providing the consumer with consumer medication information updated
to include the side effects statement. FDA is proposing that the letter
height or type size of the side effects statement be no smaller than 10
points to ensure readability. Distributing this consumer medication
information
[[Page 21782]]
with each original and refill prescription dispensed to consumers will
satisfy the requirements of this part.
e. Option 5--FDA-approved medication guides. FDA is proposing that
manufacturers include the side effects statement in FDA-approved
Medication Guides for drug products approved under section 505 of the
act. Medication Guides are typically produced by the manufacturer of
the drug product. By regulation manufacturers are required to provide
Medication Guides or the means to produce them to authorized dispensers
for distribution to the patient (Sec. 208.24). Medication Guides are
required to be printed in no smaller than 10-point letter height or
type size. Pharmacists and other authorized dispensers may comply with
this regulation by distributing Medication Guides that include the side
effects statement for those drug products approved under section 505.
Pharmacists and other authorized dispensers will need to choose a
different compliance option if an FDA-approved Medication Guide for a
drug product approved under section 505 of the act has not yet been
updated with the side effects statement, or if the prescription drug
product they are dispensing does not have a Medication Guide.
III. Legal Authority
Section 17 of the BPCA requires the agency to issue a final rule
mandating that the labeling of each drug approved under section 505 of
the act include the toll-free number for reporting adverse events
regarding drugs and a statement that the number is for reporting
purposes only, not to seek medical advice. The legislation gives FDA
broad discretion in designing the rule, requiring only that the
labeling requirement be implemented so as to reach the broadest
consumer audience and minimize the cost of the rule on the pharmacy
profession.
The proposed rule satisfies these two statutory requirements. The
proposed rule covers prescription and OTC drugs approved under section
505 of the act, and would require manufacturers, authorized dispensers,
and pharmacies to include the side effects statement on certain drug
product labeling. The scope of the proposed rule includes these
individuals and entities because they all participate in labeling drug
products approved under section 505 of the act. Drug manufacturers are
subject to comprehensive regulation of drug product labeling under the
act and its implementing regulations (e.g., 21 U.S.C. 352, 21 CFR part
201), and section 17 of the BPCA explicitly extends FDA's authority to
the side effects statement. Likewise, authorized dispensers (including
pharmacists) and pharmacies are subject to statutory labeling
requirements under section 503(b)(2) of the act, and the BPCA
contemplates that pharmacies and authorized dispensers will distribute
the side effects statement with prescription drug products approved
under section 505. Including manufacturers, authorized dispensers, and
pharmacies within the scope of the proposed rule will ensure that the
side effects statement reaches the broadest consumer audience.
FDA is proposing several compliance options for authorized
dispensers and pharmacies in order to minimize the cost of the rule on
the pharmacy profession. Of these options, authorized dispensers and
pharmacies may choose the least costly means to distribute the side
effects statement with prescription drug products. FDA recognizes that
some pharmacists voluntarily provide consumer medication information to
patients. Those who do so may put the side effects statement in that
voluntarily provided information, or they may choose to comply using
one or more of the other options the agency has proposed. The other
options include distributing the side effects statement on: (1) A
sticker attached to the unit package, vial, or container of the drug
product; (2) a preprinted pharmacy prescription vial cap; (3) a
separate sheet of paper; or (4) an FDA-approved Medication Guide, if
appropriate.
IV. Proposed Effective Date
FDA considered issuing this rule as an interim final rule to be
effective 30 days after the date of its publication in the Federal
Register. The BPCA directs FDA to issue a final rule within 1 year of
the date of the BPCA's enactment on January 4, 2002. FDA is issuing
this rule as a proposal, however, to allow the affected entities,
including manufacturers and pharmacies, to comment on the proposed
changes to the regulations.
FDA is proposing that the final rule be effective 30 days after it
is published in the Federal Register. FDA is proposing that all
manufacturers of drug products, authorized dispensers, and pharmacies
be in compliance not more than 1 year after the effective date of any
final rule published in the Federal Register. FDA anticipates that
manufacturers of drug products, authorized dispensers, and pharmacies
will require time to update labeling and systems to comply with the new
requirements.
Manufacturers of drug products that require FDA-approved Medication
Guides will need time to update these Medication Guides with the side
effects statement and to distribute them to distributors, packers, and
authorized dispensers. Manufacturers who make changes to FDA-approved
Medication Guides can submit labeling changes in annual reports as
described in Sec. 314.70(d) (21 CFR 314.70(d)) as a minor change in
labeling and need not submit a supplemental application to the agency
for preapproval.
Manufacturers of OTC drug products will require time to update OTC
labeling to make it available to consumers. Manufacturers of OTC drug
products approved under an NDA can submit their labeling changes in
their annual reports according to Sec. 314.70(d)(3) and need not
submit a supplemental application to the agency for preapproval.
Manufacturers of OTC drug products approved under an ANDA may also
submit these changes in their annual reports according to Sec.
314.70(d)(3) and Sec. 314.97 (21 CFR 314.97) and need not submit a
supplemental application to the agency for preapproval.
Pharmacies will require adequate time to make decisions about their
least-cost option to comply with the rule and either implement new
systems or update established systems. To decrease the burden of this
rule on pharmacies and authorized dispensers, as required by the BPCA,
FDA is proposing that 1 year should provide adequate time to comply
with this rule. However, FDA is soliciting comments on this proposed
compliance date.
Manufacturers of products with Medication Guides not approved under
section 505 of the act who voluntarily make changes to Medication
Guides to include the side effects statement can submit labeling
changes in annual reports as described in Sec. 601.12(f)(3)(i)(A) as a
minor change in labeling and need not submit a supplemental application
to the agency for preapproval. Manufacturers who voluntarily make
changes to PPIs required under Sec. Sec. 310.501 and 310.515 can
submit labeling changes in annual reports as described in Sec.
314.70(d) as a minor change in labeling and need not submit a
supplemental application to the agency for preapproval.
V. Analysis of Economic Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory
[[Page 21783]]
alternatives and, when regulation is necessary, to select regulatory
approaches that maximize net benefits (including potential economic,
environmental, public health and safety, and other advantages;
distributive impacts; and equity). Under the Regulatory Flexibility
Act, if a rule has a significant economic impact on a substantial
number of small entities, an agency must consider alternatives that
would minimize the economic impact of the rule on small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement of anticipated costs and
benefits before proposing any rule that may result in an expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100 million in any one year (adjusted annually for
inflation).
The agency believes that this rule is consistent with the
regulatory philosophy and principles identified in Executive Order
12866 and in these two statutes. The proposed rule would require
pharmacies and authorized dispensers to provide patients with the side
effects statement and require drug manufacturers to include the
statement on labeling of certain drug products. Potential one-time
costs of the proposed rule are projected to range from $1.3 million to
$3.7 million with annual compliance costs from $9.2 million to $22.1
million. Annualized for 10 years, total compliance costs would be
approximately $9.3 million to $22.6 million at 3 percent discount rate,
and $9.4 million to $22.6 million at 7 percent discount rate. Although
the agency is unable to quantify the potential benefits of the proposed
rule at this time, improved awareness of drug safety reporting may
increase the number of serious adverse drug reactions reported by
consumers and health care practitioners to the MedWatch program.
Potential benefits of the proposed rule are discussed in section V.B of
this document. Furthermore, the agency has determined that the proposed
rule is not an economically significant rule as described in the
Executive order, because annual impacts on the economy are
substantially below $100 million. Because the rule does not impose any
mandates on State, local or tribal governments, or the private sector
that will result in an expenditure in any one year of $100 million or
more, FDA is not required to perform a cost-benefit analysis according
to the Unfunded Mandates Reform Act. The current inflation-adjusted
statutory threshold is about $110 million. With respect to the
Regulatory Flexibility Act, the agency believes it is unlikely that
this proposed rule will result in a significant economic impact on a
substantial number of small entities.
The proposed rule would fulfill the BPCA's statutory requirement to
provide consumers with a toll-free telephone number that can be used to
report adverse drug events to FDA. The agency believes it receives
reports for only a portion of the adverse drug events that occur.
Providing consumers with this telephone number is expected to increase
public awareness of, and participation in, the agency's voluntary
adverse drug events reporting program. To ensure that the side effects
statement would cover all drug products approved under section 505 of
the act and reach a wide consumer audience as specified in the statute,
FDA proposes that labeling of OTC drug products and any required
Medication Guide for a drug product approved under section 505 must
include the side effects statement, and the side effects statement must
accompany each prescription dispensed for outpatient use. The agency
also proposes to exercise its discretion to give affected pharmacies
flexibility to select a method of compliance from among five options
that would minimize the impact of the proposed rule. For a discussion
of the alternatives FDA considered in drafting this proposed rule, see
section V.C of this document. The rule FDA proposes is the least-
expensive alternative that meets the requirements set forth in section
17 of the BPCA.
A. Costs of Regulation
1. Pharmacy Industry
Both retail and nonretail pharmacies may dispense prescription
drugs to patients. Retail channels include independent drug stores,
chain drug stores, mass merchants, grocery stores with pharmacies, and
mail/Internet services. Nonretail channels include health maintenance
organizations (HMOs), hospital outpatient pharmacies, offices of health
care practitioners, and ambulatory care clinics. Although several
sources of information about the retail pharmacy sector exist, data on
the number of ambulatory care centers or hospital outpatient
departments dispensing prescription drugs are limited.
a. Number of affected pharmacies. The proposed rule may affect all
locations where an authorized dispenser distributes prescription drug
products for outpatient use. According to the NACDS, in 2001 there were
55,581 retail pharmacies, excluding mail order businesses (Ref. 1).
Census data from 1997 show there were 314 mail order or electronic
shopping establishments with merchandise sales from prescriptions (Ref.
2). In addition, the agency tallied the number of establishments with
receipts or revenue from drug products in Health Care and Social
Assistance sectors using 1997 Economic Census data (Ref. 3). The Health
Care sector data use a single revenue code for nonprescription and
prescription drugs. Businesses with receipts or revenues from drug
products that would not be licensed to dispense prescriptions (e.g.,
chiropractors) or would be administering drugs directly to patients
(e.g., supervised home health care) were excluded from the analysis.
A study conducted for FDA found that, on average, 89 percent of
retail pharmacies currently give patients some type of written consumer
medication information (Ref. 4). It is uncertain whether this
percentage also represents nonretail pharmacies. Nevertheless, for this
analysis we assume that clinics and HMOs are similar to retail
pharmacies, distributing consumer medication information with 89
percent of the dispensed prescriptions. In addition, hospital
outpatient services and health care practitioners' offices are assumed
currently to provide no written drug information. The agency solicits
comment on these assumptions.
Whether provided by a third party vendor or prepared in-house, it
is anticipated that the side effects statement can be added to existing
databases at a negligible one-time cost. Since the statement is not
expected to increase the length of existing documents, the agency has
assumed that only pharmacies and authorized dispensers not currently
providing written consumer medication information will incur compliance
costs and be affected by the rule. FDA requests comment on this
assumption. Table 1 of this document shows the total number of
establishments dispensing prescriptions and the number anticipated to
be affected by the proposed rule.
[[Page 21784]]
Table 1.--Estimated Number of Affected Retail and Nonretail Pharmacies
------------------------------------------------------------------------
Percentage Not
Type of Total No. of Providing Written No. of Affected
Pharmacy Pharmacies Drug Information Pharmacies
------------------------------------------------------------------------
Retail Outlets ............... .................. ..................
Grocery 8,531 11% 938
Store\1\
Independent 20,647 21% 4,336
Pharmacy\1\
Mail Order/ 314 11% 35
Electronic
Shopping\2\
Mass 5,910 2% 118
Merchant\1\
Traditional 20,493 2% 410
Chain
Store\1\
------------------------------------------------------------------------
Nonretail ............... .................. ..................
Outlets:
HMO Medical 209 11% 23
Center\3,4\
Hospital 5,878 100% 5,878
Outpatient
Service\3,5\
Office of 7,867 100% 7,867
Health Care
Practitioner
\3,6\
Outpatient 1,881 11% 207
Care Center,
except
HMO\3,7\
------------------------------------------------------------------------
Total of all 71,730 .................. 19,812
Affected
Outlets
------------------------------------------------------------------------
\1\ Source: Ref. 1.
\2\ Source: Ref. 2, Table 2. Includes number of establishments in North
American Industry Classification System (NAICS) code 454110 with
merchandise sales for code 0161.
\3\ Source: Ref. 3, Tables 1a and 1b.
\4\ Includes number of establishments in NAICS 621491 with receipts or
revenue from code 8619. Excludes nonemployer statistics.
\5\ Includes number of establishments in NAICS 622 with receipts or
revenue from outpatient services (code 5250). Excludes nonemployer
statistics.
\6\ Includes number of establishments in NAICS 62111, 62121, 62132,
62139, with receipts or revenue from code 8619. Excludes nonemployer
statistics.
\7\ Includes number of establishments in NAICS 62141, 62142, 621492,
621493, 621498, with receipts or revenue from code 8619. Excludes
nonemployer statistics.
b. Prescriptions dispensed. For those pharmacies not providing
written consumer medication information, the compliance costs of the
proposed rule would be proportional to the number of outpatient
prescriptions that affected pharmacies dispense annually. Consequently,
smaller pharmacies dispensing fewer prescriptions than larger
pharmacies would incur lower costs. Moreover, the proposed rule
requires distributing the side effects statement with both new and
refill prescriptions. Since individuals with multiple chronic
conditions could potentially receive the side effects statement many
times each year, the agency solicits comment on whether the statement
could be distributed less frequently to this subset of individuals
without increasing the burden on pharmacies.
IMS Health collects data on the number of prescriptions dispensed
as well as the number of pharmaceutical products purchased by the
retail channels. In contrast, only data on the number of products
purchased by nonretail channels are available. Because the types of
drugs and dosage forms dispensed to outpatients are expected to be
similar for retail and nonretail channels, the agency uses IMS data
from both channels to derive estimates of the number of prescriptions
dispensed annually by nonretail pharmacies (IMS Health, National
Prescription Audit Plus, Provider Perspective, Retail Perspective, see
appendix for details). Based on volume from 2001, pharmacies are
estimated to dispense between 3.28 billion and 3.64 billion
prescriptions to outpatients each year (table 2 of this document).
However, this number is expected to increase over time. Estimates from
NACDS predict that future drug use will increase approximately 26
percent by the year 2005 (Ref. 1). The agency requests comment on these
estimates.
BILLING CODE 4160-01-S
[[Page 21785]]
[GRAPHIC] [TIFF OMITTED] TP22AP04.002
BILLING CODE 4160-01-C
[[Page 21786]]
c. Compliance costs for pharmacies. The proposed rule provides
several compliance options, allowing pharmacies and authorized
dispensers flexibility to select the least costly compliance method.
The proposed rule describes five ways pharmacies and authorized
dispensers can distribute the side effects statement to patients. These
methods may be used individually or together in any combination, and
include: (1) Attaching a standard-size sticker to the prescription
container, (2) distributing a separate sheet of paper, (3) distributing
consumer medication information containing the side effects statement,
(4) using an imprinted vial cap, or (5) distributing the appropriate
FDA-approved Medication Guide. Moreover, the widespread and growing use
of electronic communication presents the opportunity to innovatively
inform consumers about public health. FDA solicits suggestions on
possible electronic methods to distribute the side effects statement
that would comply with the BPCA's statutory mandate, and comment on
what burden such solutions might impose on pharmacies and drug
manufacturers. FDA also requests comment on whether electronic means of
distributing the side effects statement would be consistent with the
statutory definition of ``labeling.''
The magnitude of the compliance costs will depend on whether a
pharmacy is currently using one or more of these methods. For example,
although third party vendors of consumer medication information
software would incur negligible one-time costs modifying their
databases to include the side effects statement, FDA believes that
pharmacies using this type of software will incur no additional costs.
Similarly, if a drug information database is managed in-house and the
pharmacy is already handing out consumer medication information to
patients, only a negligible one-time cost to add the statement may be
incurred. For prescription drug products with Medication Guides,
pharmacies and authorized dispensers will incur no additional costs
since they are already required to distribute Medication Guides with
those products. Outlets already using imprinted vial caps that elect to
add the statement to the cap may incur negligible one-time costs to
prepare a new stamping template. In contrast, switching from a non-
imprinted vial cap to one imprinted with the side effects statement
might increase the cost of each vial cap by an estimated 15 percent.
Some pharmacies, however, might incur new costs for each
prescription they dispense. To illustrate the potential impact, the
agency calculates the associated costs to affix a sticker, preprinted
with the statement, on the prescription container. The agency believes
that this option reflects the highest potential cost of the proposed
rule to pharmacies and authorized dispensers. A box of series 1
preprinted stickers contains 1,000 stickers at a cost of $2.90, or
$0.003 per sticker. In addition to the cost of the sticker, pharmacy
personnel may spend about 5 minutes per 1,000 stickers for ordering and
inventory control and 5 seconds to affix each sticker to the container.
Although in some small establishments a pharmacist may perform these
tasks, a pharmacy technician or pharmacy school intern would probably
perform these actions. Therefore, a range of labor costs are calculated
with a pharmacy technician's mean and 90 percentile loaded hourly wage
rates of $14.53 and $20.38, respectively, including 40 percent for
benefits (Ref. 5). The annual costs of the proposed rule for affected
retail pharmacies may range from $6.4 million to $8.7 million, and from
$2.8 million to $11.5 million for nonretail pharmacies. If the entire
affected pharmacy industry complied using this option, the proposed
rule may cost from $9.2 to $20.2 million annually (table 3 of this
document).
Pharmacies could also elect to hand out a piece of paper printed
with the side effects statement. Costs for this option depend on the
size and quality of the paper. However, based on retail prices, a
single sheet of paper and the ink to print the side effects statement
cost approximately $0.013. A sheet of paper can comfortably accommodate
from 8 to 20 statements in 10-point font, depending on the spacing
between statements. Thus, the per statement cost of materials for this
option ranges from about $0.001 to $0.002, substantially less than the
sticker option. However, because the time required to cut up a piece of
paper and distribute it with the prescription may exceed the time
needed to affix a sticker, the average total cost to distribute a piece
of paper is anticipated to be similar to the average total cost of the
sticker option.
Table 3.--Potential Compliance Costs for Pharmacies\1\
----------------------------------------------------------------------------------------------------------------
Cost of
Type of Pharmacy No. of Affected Average No. of Stickers ($ Labor Costs ($ Total Cost ($
Outlets Dispensed Rx\2\ mil) mil) mil)
----------------------------------------------------------------------------------------------------------------
Retail Outlets: .................. ............... ............... ............... ...............
Grocery Store 938 49,997 $0.14 $1.00 to $1.41 $1.14 to $1.54
Independent Pharmacy 4,336 37,714 $0.47 $3.50 to $4.91 $3.97 to $5.38
Mail Order or 35 520,732 $0.05 $0.38 to $0.54 $0.44 to $0.59
Electronic Shopping
Mass Merchant 118 52,623 $0.02 $0.13 to $0.19 $0.15 to $0.20
Traditional Chain 410 69,194 $0.08 $0.61 to $0.85 $0.69 to $0.93
Store
----------------------------------------------------------------------------------------------------------------
Retail Subtotal 5,837 ............... $0.76 $5.63 to $7.89 $6.39 to $8.66
----------------------------------------------------------------------------------------------------------------
Nonretail Outlets: .................. ............... ............... ............... ...............
HMO Medical Center 23 79,244 to $0.01 to $0.01 $0.04 to $0.08 $0.04 to $0.09
121,688
Hospital Outpatient 5,878 16,704 to $0.28 to $0.92 $2.10 to $9.52 $2.39 to $10.44
Service 53,947
Offices of Health Care 7,867 1,042 to 1,171 $0.02 to $0.03 $0.18 to $0.28 $0.20 to $0.30
Practitioner
Outpatient Care 207 33,262 to $0.02 to $0.06 $0.15 to $0.64 $0.17 to $0.70
Center, except HMO 103,126
----------------------------------------------------------------------------------------------------------------
Nonretail Subtotal 13,975 ............... $0.33 to $1.02 $2.46 to $10.52 $2.80 to $11.53
----------------------------------------------------------------------------------------------------------------
[[Page 21787]]
Industry Total 19,812 ............... $1.10 to $1.78 $8.09 to $18.41 $9.19 to $20.19
----------------------------------------------------------------------------------------------------------------
\1\ Totals may not sum due to rounding.
\2\ Average number of dispensed Rx calculated by dividing the number of prescriptions dispensed in Table 2 of
this document by the total number of pharmacies in Table 1 of this document.
2. Drug Manufacturers
a. Number of affected products. The proposed rule requires that,
within 1 year of the effective date of the final rule, manufacturers of
OTC drugs approved under section 505 of the act add the side effects
statement to drug product labeling, and manufacturers of any
prescription drug product with an FDA-approved Medication Guide add the
side effects statement to that Medication Guide. The agency estimates
that the rule may affect approximately 522 OTC products, including 350
branded and 172 private label products, and up to 18 prescription drug
products with Medication Guides.
b. Cost to modify product labeling. The proposed rule requires that
the side effects statement be included in the ``Warning(s)'' section of
the ``Drug Facts'' box, adding 101 characters to drug product labeling.
Because of the brevity of the statement, the agency anticipates that
manufacturers of the affected products may incur a one-time cost to
modify labeling, but no additional incremental printing or packaging
modification costs. The agency solicits comment on this assumption. OTC
products marketed under NDAs or ANDAs usually have 2 to 3 stockkeeping
units (SKUs), suggesting that up to 1,050 branded packages and 520
private label packages might be affected by the final rule. Revising
labeling of branded OTC products may cost about $3,000 for each branded
SKU and $1,000 for each private label SKU. Because nonprescription drug
manufacturers often use the packaging of OTC products to market their
products and change labeling frequently, some labeling costs of the
proposed rule would be incurred in the normal course of business. Thus,
the per SKU cost estimates are an upper bound. New compliance costs for
nonprescription drug manufacturers may range from $1.2 million with one
SKU per affected product to $3.7 million with three SKUs per affected
product. The agency solicits comment on the number of SKUs affected by
the proposed rule and the potential new compliance costs to revise the
product labeling of these SKUs.
Manufacturers of prescription drug products change labeling less
frequently than OTC manufacturers and therefore may also incur some
excess inventory loss because of the 12-month implementation period.
Including excess inventory loss and scrap of $1,463, adding the
statement to Medication Guides may cost manufacturers an average of
$4,177 per product. Within the first year, OTC and prescription drug
manufacturers together might incur one-time costs from $1.3 million to
$3.7 million to comply with the proposed rule. Annualized for 10 years,
compliance costs would range from $0.2 million to $0.4 million at 3
percent discount rate, and from $0.2 million to $0.5 million at 7
percent discount rate.
3. Burden on FDA
Approximately 100 calls are received each week by the MedWatch
program. When a consumer contacts the agency directly by telephone, a
MedWatch 3500 form and instructions are mailed. Because some questions
on the MedWatch 3500 form request clinical information, the
instructions recommend that patients work with their health care
practitioner to complete the form. However, the confidential nature of
the reporting program makes it difficult to track the number of forms
consumers return to the agency. In 2001, consumers submitted 1,788
direct reports. This suggests that roughly one-third of the mailed
forms are returned.
It is uncertain if receiving the side effects statement with
dispensed prescriptions will cause more consumers to call the MedWatch
program and report their drug side effects. According to an agency
communications specialist, it is likely that some consumers may call
the toll-free number with questions or comments unrelated to the
intended purpose of safety reporting. Moreover, health care
practitioners can report serious adverse drug events to the agency by
telephone. From 1998 to 2001, an average of 718 such telephone reports
were submitted annually. Even though health care practitioners are not
the direct focus of the proposed rule, it is possible that the rule may
cause an increase in direct reporting from health care practitioners.
Although the agency cannot predict the additional number of calls and
reports that might result from the proposed rule, the impact on the
agency could be substantial.
It costs the agency an average of $5.60 for each consumer call to
the MedWatch program to answer the telephone, process the call, and
mail the MedWatch form. Once the MedWatch form is returned, the agency
may spend up to $25.00 processing the form and entering the data in the
Adverse Events Reporting System (AERS). If only one-third of the calls
to MedWatch produce an adverse drug event report, each consumer report
would cost the agency about $41.80. However, if every telephone call
produces a consumer report, the per report cost decreases to $30.60.
Furthermore, reports submitted directly to the MedWatch Website would
only cost $25 since there are not additional costs to answer and
process the telephone call. Moreover, if there is a substantial
increase in the number of telephone calls, the agency might also incur
fixed costs for additional telephone and computer equipment.
MedWatch data suggest that telephone reports from practitioners
account for approximately 5 percent of the direct reports submitted by
mail, facsimile, or telephone. In contrast to consumer reports,
telephone reports from health care practitioners may take up to 1.25
hours to process, costing the agency an estimated $67.31 ($53.85 per
hour x 1.25 hours). However, the agency does not know the number and
source of new direct calls and reports it might receive in response to
this rule. Therefore, table 4 presents five scenarios to illustrate the
possible impact of the proposed rule on the agency if the volume of
consumer calls increased by approximately 0.05 percent, 1 percent, 50
percent, 500 percent, or 1,000 percent over current levels. Because the
3-to-1 relationship of calls to reports could vary, each
[[Page 21788]]
scenario shows the impacts on the agency with a range of 1 to 3 calls
for each direct report submitted to MedWatch by consumers. Variable
costs for FDA could range from $42 to $1,923,308 annually. The agency
solicits comments from industry on their experience with consumer
telephone calls to toll-free numbers and the proportion of the calls
related to safety issues.
Table 4.--Potential Annual Cost of Increased Direct Calls and Reports to FDA's MedWatch Program\1\
----------------------------------------------------------------------------------------------------------------
Potential Scenarios\2\
-------------------------------------------------------------------------------
1 2 3 4 5
----------------------------------------------------------------------------------------------------------------
No. of Additional Calls Received 3 60 3,000 30,000 60,000
----------------------------------------------------------------------------------------------------------------
No. of Additional Reports 1 to 3 20 to 60 1,000 to 3,000 10,000 to 20,000 to
Returned by Mail or Fax 30,000 60,000
----------------------------------------------------------------------------------------------------------------
Potential Cost for Additional $42 to $92 $836 to $1,836 $41,800 to $418,000 to $836,000 to
Calls and Direct Reports\3\ $91,800 $918,000 $1,836,000
----------------------------------------------------------------------------------------------------------------
No. of Telephone Reports from 0 1 50 500 1,000
Health Care Practitioners\4\
----------------------------------------------------------------------------------------------------------------
Potential Cost for Telephone $0 $87 $4,365 $43,654 $87,308
Reports from Practitioners
----------------------------------------------------------------------------------------------------------------
Total Potential Annual Cost $42 to $92 $923 to $1,923 $46,165 to $461,654 to $923,308 to
$96,165 $961,654 $1,923,308
----------------------------------------------------------------------------------------------------------------
\1\ Roughly one-third of the MedWatch calls from consumers result in a completed report being returned to FDA.
However, calls from other sources may have better yields than calls from consumers. A new telephone call might
yield between one and three new reports. Because of this uncertainty, each scenario presents a range of
potential costs that could be associated with an increase in the number of telephone calls to MedWatch.
\2\ Totals may not sum or multiply due to rounding.
\3\ This estimate assumes that all direct consumer reports would be initiated by telephone calls to the MedWatch
program and may overstate the potential costs if a substantial number of reports are submitted via the
Internet.
\4\ Based on FDA data, approximately 5 percent of direct reports received from sources other than the Internet
are telephone reports from health care providers. Estimate corresponds to 5 percent of the lower limit of the
potential number of new reports.
4. Total Potential Costs of Proposed Rule
As illustrated previously, affected pharmacies and authorized
dispensers may incur negligible one-time costs or increased annual
costs, FDA may incur increased annual costs, and affected drug
manufacturers and third party vendors of consumer medication
information may incur one-time costs in the 12 months following the
effective date. Table 5 summarizes the range of potential costs of the
rule. The agency requests comment on these estimates.
Table 5.--Summary of Compliance Costs of Proposed Rule\1\
----------------------------------------------------------------------------------------------------------------
Annualized Costs ($mil)
Affected Sector One-Time Costs ($ mil) Annual Costs ($ mil) ---------------------------
3 percent 7 percent
----------------------------------------------------------------------------------------------------------------
Retail Pharmacies ........................ $6.4-$8.7 $6.4-$8.7 $6.4-$8.7
----------------------------------------------------------------------------------------------------------------
Nonretail Pharmacies ........................ $2.8-$11.5 $2.8-$11.5 $2.8-$11.5
----------------------------------------------------------------------------------------------------------------
Drug Manufacturers $1.3-$3.7 ........................ $0.2-$0.4 $0.2-$0.5
----------------------------------------------------------------------------------------------------------------
PPI Vendors $0.0 ........................ $0.0 $0.0
----------------------------------------------------------------------------------------------------------------
FDA ........................ $0.0-$1.9 $0.0-$1.9 $0.0-$1.9
----------------------------------------------------------------------------------------------------------------
Total $1.3-$3.7 $9.2-$22.1 $9.3-$22.6 $9.4-$22.6
----------------------------------------------------------------------------------------------------------------
\1\Totals may not sum due to rounding.
B. Benefits of Regulation
The proposed rule would alert patients receiving prescription
products to contact their doctor for medical advice about drug side
effects and would provide a toll-free telephone number to report side
effects to FDA.
All drug products have risks as well as benefits. Every year over
100 NDAs, including about 30 for new molecular entities, are approved
in the United States (Ref. 6). Initial approval is based on the risks
and benefits identified during the clinical trial phase of drug
development. Although designed to detect common serious adverse drug
reactions, premarketing clinical trials are not sufficiently large to
detect very rare adverse events. Some uncertainty about the risks of
approved drugs will always exist, requiring a system of postmarketing
surveillance. In the United States, the agency's MedWatch program
provides the mechanism for health care professionals and patients to
voluntarily report serious adverse events and product problems.
Many adverse drug events in the outpatient setting are not
systematically tracked and recorded. The agency
[[Page 21789]]
estimates it receives reports of between 1 and 10 percent of the actual
adverse drug events that occur (Ref. 7). While drug manufacturers are
required to notify FDA of certain adverse drug events, reports from
individuals and health care professionals are voluntary. Consumers
submitted only 8 percent of the 22,645 voluntary (i.e., direct) reports
received by the agency in 2001. Increasing patient awareness of the
MedWatch program may enhance patient participation. Moreover, since the
agency encourages patients to report serious side effects through their
provider, the proposed rule may also increase reporting from health
care practitioners.
Drug-related illness costs society billions of dollars in direct
medical care and lost productivity every year. Results of a large study
of hospital discharge records conducted in Utah and Colorado suggest
that adverse drug events cost society at least $42.5 billion each year
of which only $18.5 billion would be considered preventable medication
errors (Ref. 8). A recent revision of the 1995 Johnson and Bootman
cost-of-illness model predicts that drug-related morbidity and
mortality occurring in ambulatory care settings cost about $177.4
billion each year (Ref. 9).
The agency has no quantitative information about the value of
additional drug safety reports that it might receive once the toll-free
number is widely distributed to the public. Reports of adverse drug
events provide the agency with ``signals'' that a drug product might
have previously unidentified risks. Once a signal is detected, the
agency can decide whether further action is necessary to protect public
health. The proposed rule has the potential to increase the number of
direct reports being submitted, thereby providing the agency with more
data about potential serious adverse drug events. Having more data may
make it easier for the agency to detect signals about previously
unknown risks of drugs. However, it is also possible that the toll-free
number will encourage calls unrelated to drug product safety. Because
the number and nature of calls that will be generated by the toll-free
number are unknown, the agency cannot quantify the potential benefits
of this rule. Moreover, findings of studies on the effectiveness of
warning labels suggest that adding an additional sticker to an
overcrowded prescription vial could dilute the impact of existing
warnings (Ref. 10). Therefore, the agency solicits comment on the
potential effects that could be anticipated from this rule.
C. Impact on Small Entities
1. The Need for the Proposed Rule
The Regulatory Flexibility Act requires the agency justify the need
for the proposed rule. As described previously, the proposed rule
fulfills the statutory requirement of the BPCA to provide consumers
with a toll-free telephone number to report adverse drug events to FDA,
along with a statement that the number is not to seek or obtain medical
advice.
2. Description of the Affected Small Entities
a. The pharmacy industry. The proposed rule will affect pharmacies
and authorized dispensers in both the Retail Trade sector and the
Health Care and Social Assistance sector that dispense prescriptions to
outpatients. For the purposes of this initial regulatory flexibility
analysis, affected firms are considered small if they are: (1) A for-
profit firm that meets the definition of small according to the current
Small Business Administration (SBA) industry size standards; (2) an
independently owned and operated, not-for-profit enterprise that is not
dominant in its field; or (3) operated by a small governmental
jurisdiction with a population of less than 50,000 individuals. Since
SBA size standards differ from Census size categories, in the retail
sector, all for-profit firms with receipts less than the Census size
shown in table 6 of this document are considered small. Using Census
data will slightly overestimate the number of small entities.
Although the agency knows of no data on the number of small retail
entities dispensing pharmaceutical drugs, the Census Bureau reports the
number of establishments with prescription drugs as a merchandise line,
and the number of firms by annual sales categories. If the proportion
of establishments with merchandise sales from prescription drugs is
uniform across all size firms, approximately 26,621 small entities may
dispense prescriptions. Furthermore, if the proportions in Table 1 of
this document also apply equally to small entities (i.e., the
proportion not currently distributing written drug information),
approximately 4,879 small retail firms would be affected by the
proposed rule (table 6 of this document). FDA solicits comment on these
assumptions.
Table 6.--Estimated Number of Affected Small Retail For-Profit Entities
----------------------------------------------------------------------------------------------------------------
No. of Estimated
Census SBA Size No. of Share With Small No. of
Description of Business and NAICS Code Size ($ Standard Small Sales From Entities Affected
mil) ($ mil) Entities\1\ Rx\2\ With Sales Small
From Rx Entities
----------------------------------------------------------------------------------------------------------------
Supermarkets and other grocery stores, $25.0 $23.0 36,728 17.8% 6,543 720
except convenience (445110)
----------------------------------------------------------------------------------------------------------------
Convenience stores (445120) $25.0 $23.0 17,159 1.9% 320 35
----------------------------------------------------------------------------------------------------------------
Pharmacies and drug stores (4461101) $10.0 $6.0 19,516 100.0% 19,516 4,098
----------------------------------------------------------------------------------------------------------------
Discount or mass merchandising $25.0 $23.0 28 47.6% 13 0
department stores, excluding leased
(4521102)
----------------------------------------------------------------------------------------------------------------
Electronic shopping and mail-order $25.0 $21.0 7,314 3.1% 229 25
houses (454110)
----------------------------------------------------------------------------------------------------------------
Total .......... .......... 80,745 .......... 26,621 4,879
----------------------------------------------------------------------------------------------------------------
\1\ Source: Table 4 in Ref. 11. May include small entities that do not dispense pharmaceutical drugs.
\2\ Equals the percent of all establishments in the NAICS with sales from merchandise line code 0161 (i.e.,
prescriptions). Source: Table 2 in Ref. 2.
[[Page 21790]]
In the Health Care and Social Assistance sector, both for-profit
and not-for-profit entities may dispense prescriptions for outpatient
use and would therefore be affected by the proposed rule. Census data
exist on the number of establishments with receipts and revenues from
prescription or nonprescription drugs as well as on firm size data.
Table 7 of this document summarizes the estimated number of small for-
profit firms with receipts from prescription or nonprescription drugs,
and firms anticipated to be affected by the rule. Based on the Census
receipt size most closely matching the SBA size standard and the share
of for-profit establishments with receipts from prescription or
nonprescription drugs (i.e., Receipt Line (RL) code 8619), there are
approximately 6,855 small for-profit entities in this sector. (Again,
using Census data slightly overestimates the number of small entities.)
Applying the proportion of affected firms from table 1 of this
document, an estimated 6,577 small for-profit firms may be affected by
the rule.
Table 7.--The Number of Affected Small For-Profit Nonretail Entities
----------------------------------------------------------------------------------------------------------------
Share of
All No. of Estimated
Census SBA Size No. of Nonretail Small No. of
Description of Business and NAICS Code Size ($ Standard Small Outlets Entities Affected
mil) ($ mil) Entities\1\ With With Small
Receipts Receipts Entities
From Rx\2\ From Rx
----------------------------------------------------------------------------------------------------------------
Offices of physicians (62111) $10.0 $8.50 151,479 2.8% 4,177 4,177
----------------------------------------------------------------------------------------------------------------
Offices of dentists (62121) $10.0 $6.00 101,932 1.3% 1,280 1,280
----------------------------------------------------------------------------------------------------------------
Offices of optometrists (62132) $10.0 $6.00 14,570 3.0% 441 441
----------------------------------------------------------------------------------------------------------------
Offices of other health care $10.0 $6.00 11,678 3.5% 404 404
practitioners (62139)
----------------------------------------------------------------------------------------------------------------
Family planning centers (62141) $10.0 $8.50 273 9.0% 25 3
----------------------------------------------------------------------------------------------------------------
Outpatient mental health & substance $10.0 $8.50 1,507 2.3% 35 4
abuse centers (62142)
----------------------------------------------------------------------------------------------------------------
HMO medical centers (621491) $10.0 $8.50 14 19.8% 3 0
----------------------------------------------------------------------------------------------------------------
Kidney dialysis centers (621492) $50.0 $29.00 355 25.9% 92 10
----------------------------------------------------------------------------------------------------------------
Free-standing ambulatory surgical & $10.0 $8.50 1,235 9.5% 117 13
emergency centers (621493)
----------------------------------------------------------------------------------------------------------------
Other outpatient care centers (621498) $10.0 $8.50 1,891 2.2% 42 5
----------------------------------------------------------------------------------------------------------------
Hospital outpatient services (622) $50.0 $29.00 282 85.0% 240 240
----------------------------------------------------------------------------------------------------------------
Total .......... .......... 285,216 .......... 6,855 6,577
----------------------------------------------------------------------------------------------------------------
\1\ Source: Table 4a in Ref. 12. May include small entities that do not dispense prescription drugs.
\2\ Equals the percent of all establishments in the NAICS with receipts from code 8619 (i.e., prescription and
nonprescription drugs). Source: Table 1a in Ref. 3.
Similar to the table on the number of for-profit small entities in
the Health Care sector, table 8 of this document summarizes the
estimated number of small not-for-profit firms. For this analysis,
single-unit firms exempt from Federal income tax are treated as small.
This definition of a small entity may overstate the number of small,
government, hospital-based outpatient clinics since some single-unit
hospitals are located in jurisdictions with populations larger than
50,000. Similar to other outlets in the Health Care sector, not-for-
profit firms dispensing drugs are assumed to be equally distributed
across all firm sizes. Therefore, based on the 1997 Economic Census
data, about 2,085 small not-for-profit entities may dispense drugs
(i.e., have revenues from RL code 8619). Applying the Table 1
proportions, the proposed rule is estimated to affect 1,834 of these
small entities.
Table 8.--The Number of Affected Small Not-for-Profit Nonretail Entities
----------------------------------------------------------------------------------------------------------------
Share of All No. of Small
Not-for-Profit Not-for-Profit Estimated No.
Description of Business and NAICS Code No. of Small Outlets With Entities With of Affected
Entities\1\ Revenues From Revenues From Small Not-for-
Rx\2\ Rx Profit Entities
----------------------------------------------------------------------------------------------------------------
Family planning centers (62141) 454 39% 176 19
----------------------------------------------------------------------------------------------------------------
Outpatient mental health & substance abuse 698 1% 5 1
centers (62142)
----------------------------------------------------------------------------------------------------------------
HMO medical center (621491) 2 31% 1 0
----------------------------------------------------------------------------------------------------------------
Kidney dialysis centers (621492) 9 8% 1 0
----------------------------------------------------------------------------------------------------------------
Freestanding ambulatory surgical & emergency 55 6% 3 0
centers (621493)
----------------------------------------------------------------------------------------------------------------
[[Page 21791]]
Other outpatient care centers (621498) 984 10% 96 11
----------------------------------------------------------------------------------------------------------------
Hospital outpatient services (622) 2,033 89% 1,803 1,803
----------------------------------------------------------------------------------------------------------------
Total 4,235 ............... 2,085 1,834
----------------------------------------------------------------------------------------------------------------
\1\ Source: Table 3b in Ref. 12. May include small single unit firms that do not dispense prescription drugs.
\2\ Equals the percent of all establishments in the NAICS with revenues from code 8619 (i.e., prescription and
nonprescription drugs). Source: Table 1b in Ref. 3.
Most pharmacies and authorized dispensers currently distribute
information to patients using at least one of the five proposed
compliance methods. These small entities would incur only negligible
one-time costs to add the side effects statement and would not require
any additional skills. The agency requests comment on these
assumptions. Although pharmacies can choose the least-cost compliance
method from among five options, about 11 percent of pharmacies that
currently do not distribute consumer medication information to patients
could incur new annual costs to comply with the proposed rule. These
costs would be proportional to the number of prescriptions dispensed.
Because all options involve tasks normally performed in a pharmacy, no
additional skills would be required. FDA believes adding a preprinted
sticker with the side effects statement would likely be the most costly
means of compliance. The agency estimates that adding a preprinted
sticker with the statement to a prescription container would cost up to
$0.03 per prescription. NACDS reports that in 2001, retailer pharmacies
received approximately $10.57 for the average prescription costing
$50.17 (Ref. 1). Adding a sticker might reduce affected retail pharmacy
revenues by 0.3 percent. FDA believes this would not result in a
significant economic impact on a substantial number of small retail
pharmacies.
b. Drug manufacturers. The proposed rule will also affect drug
manufacturers of products with Medication Guides or OTC products
approved under section 505 of the act. According to the SBA size
standards, Pharmaceutical Preparation Manufacturing firms (NAICS
325412) with fewer than 750 employees are considered small. Since the
Census Bureau uses different employment size categories than the SBA,
the number of small entities is based on the percentage of
establishments with less than 1,000 employees. According to this
definition, 97 percent of all establishments operating in 1997 were
small (Ref. 13). If a similar share of firms in this sector are small,
1999 data suggest there could be up to 730 small entities in this
sector (Ref. 14).
Small manufacturers of drug products with FDA-approved Medication
Guides may incur an average of $3,165 in one-time costs to revise
labeling of each affected product. Table 9 of this document illustrates
the possible impacts on these manufacturers. Depending on production
volume, the annualized costs of the proposed rule will add between
$0.005 and $0.45 per unit sold. Moreover, NACDS reports that
manufacturers receive $37.93 of the average $50.17 cost of a
prescription (Ref. 1). If this figure is representative for the small
entities affected by the rule, the additional annualized cost might
reduce average receipts by less than 1.25 percent. FDA requests
comments on these estimates from affected small entities.
Manufacturers of affected OTC products may spend between $1,000 and
$3,000 to change their labeling. The effect on individual firms will
vary with the number of products the firm must modify. The agency
cannot assess the economic impact of the proposed rule on the small OTC
manufacturers because Census does not report sales data for OTC
products sold through all markets. However, most small firms
manufacture few affected stock keeping units and might not incur
significant regulatory costs. The agency requests comment from affected
small entities.
Table 9.--Estimated Cost for Small Entities with Three Alternative
Levels of Production
------------------------------------------------------------------------
No. of Units, With Medication Guides, Sold Annually
-----------------------------------------------------------
1,000 10,000 100,000
------------------------------------------------------------------------
Annualized $450.58 $450.58 $450.58
cost to
revise
labeling\1\
------------------------------------------------------------------------
Additional $0.45 $0.05 $0.005
cost per
unit sold
------------------------------------------------------------------------
Additional 1.19% 0.12% 0.01%
cost per
unit sold
as a
percentage
of average
manufacture
r's share
of retail
prescriptio
n cost\2\
------------------------------------------------------------------------
\1\ $450.58 equals the $3,164.71 one-time cost, annualized at 7% for 10
years.
\2\ Based on an average share of $37.93 (Ref. 1).
As a result of this analysis, FDA believes that this proposed rule
would not have a significant economic impact on a substantial number of
small entities.
c. Alternatives considered.
Alternative implementation schedule
Because of the requirements of the BPCA, FDA considered a shorter
implementation schedule, requiring compliance within 6 months of the
effective date of the rule. However, the BPCA also mandates action that
minimizes the cost on pharmacies and reaches the broadest consumer
[[Page 21792]]
audience. To address all of these requirements, the agency selected a
1-year implementation plan. This longer period will provide adequate
time for all affected establishments to comply with the rule and
specifically reduce the cost burden on small entities.
Require side effects statement for all drug labeling
The agency considered, but rejected, requiring that the side
effects statement be added to the ``physician labeling'' of all
prescription drug products. The BPCA requires that the statement reach
the broadest consumer audience possible. Physician labeling is targeted
to health care practitioners and pharmacists. Although consumers may
have access to this labeling, it is not intended for the consumer
audience. Thus, adding the statement to physician labeling would cause
firms of all sizes to incur costs that would not be necessary to
achieve the goal of reaching a broad consumer audience.
Furthermore, the agency has proposed changes to physician labeling
that will require drug manufacturers to include contact information,
including the MedWatch telephone number, so that health care
practitioners may report serious adverse drug reactions. These proposed
changes will inform consumers who do access physician labeling how to
report adverse events to FDA. If the proposed rule also required that
firms add the side effects statement to physician labeling, many firms
might be required to change labeling twice in a short period of time.
This could be especially burdensome on small entities.
The one-time cost of this alternative would be approximately $15.6
million, including any excess inventory losses with a 1-year
implementation schedule. However, allowing firms additional time to
change labeling would reduce the costs of this alternative. For
example, following a schedule staggered over 7 years after the
effective date, similar to that proposed for the physician labeling
rule, reduces the one-time cost of this alternative to $12.7 million
with a present value of $8.0 million. Moreover, with a longer
implementation schedule, some firms could avoid these compliance costs
by adding the side effects statement when they revise drug product
labeling for other reasons.
The agency also considered, but rejected, requiring the side
effects statement to be included in PPIs. However, because not all
prescription drug products carry PPIs, FDA determined that it was not
the most effective way to reach a broad consumer audience, and would be
duplicative of other methods the agency is proposing to distribute the
side effects statement.
Alternative statement
FDA considered but rejected several alternatives for the proposed
side effects statement. The agency considered a more comprehensive side
effects statement to clarify when consumers should call FDA. The agency
also considered requiring that the side effects statement be formatted
in a larger type size than currently proposed for the sticker and vial
cap options. The agency determined that these alternatives would
require pharmacies to use larger, nonstandard stickers, thereby
increasing compliance costs. The agency is proposing a more succinct
side effects statement and smaller type size for the sticker and vial
cap options in order to reduce the burden on small entities.
Options for pharmacies and authorized dispensers
FDA considered several options pharmacies and authorized dispensers
could use to satisfy the requirements of the proposed rule. FDA has
included all of these options in its proposal in order to minimize the
effects of the rule on the pharmacy profession.
VI. Paperwork Reduction Act
FDA tentatively concludes that this proposed rule contains no
collections of information. Therefore, clearance by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(the PRA) (Public Law 104-13) is not required. FDA is proposing to
amend its regulations to require a labeling statement be added to
certain categories of drug product labeling. The proposed labeling
statement for prescription drugs products is, ``Call your doctor for
medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.'' For OTC drug products approved under section 505
of the act, the agency is proposing to use the existing subheading in
Sec. 201.66(c)(5)(vii) that states, ``Stop use and ask a doctor if,''
followed by the bulleted statement ``side effects occur.'' The second
sentence would remain the same as for prescription products: ``You may
report side effects to FDA at 1-800-FDA-1088.'' These labeling
statements are not subject to review by OMB because they are
``originally supplied by the Federal Government to the recipient for
the purpose of disclosure to the public'' (5 CFR 1320.3(c)(2)) and are
not considered a collection of information under the PRA.
VII. Environmental Impact
The agency has considered the environmental effects of this
proposed rule and has determined under 21 CFR 25.30(h) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
VIII. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
the agency has concluded that the proposed rule does not contain
policies that have federalism implications as defined in the Executive
order and, consequently, a federalism summary impact statement is not
required.
IX. Request for Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES). Two paper copies of any written comments are to be
submitted, except that individuals submitting written comments or
anyone submitting electronic copies may submit one paper copy. Comments
are to be identified with the docket number found in brackets in the
heading of this document. Received comments may be seen in the Division
of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
X. References
The following references have been placed on display in the
Division of Dockets Management and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday. (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.)
1. ``2001 Industry Facts-at-a-Glance,'' National Association of
Chain Drug Stores, http://www.nacds.org (last viewed October 24,
2002).
2. ``Summary 1997 Economic Census, Retail Trade,'' U.S.
Department of Commerce, U.S. Census Bureau, Publication No.
EC97R44S-SM, January 2001, pp. 55, 57, 69, 122, 151.
3. ``Sources of Receipts or Revenue, 1997 Economic Census,
Health Care and Social Assistance, Subject Series,'' U.S. Department
of Commerce, U.S. Census Bureau, Publication No. EC97S62S-LS, August
2000, pp. 7-9, 11-13, 16, 24-27, 29.
[[Page 21793]]
4. Svarstad, B. et al., ``Evaluation of Written Prescription
Information Provided in Community Pharmacies, 2001,'' Final report
to FDA, December 21, 2001, presented at the FDA Drug Safety and Risk
Management Advisory Committee Meeting, July 17, 2002, http://www.fda.gov/cder/reports/prescriptionInfo/default.htm (last viewed
October 21, 2002).
5. 2000 National Occupational Employment and Wage Estimates,''
U.S. Department of Labor, Bureau of Labor Statistics, http://www.bls.gov.oes/2000/oes292052.htm (last viewed April 28, 2003).
6. Friedman, M. A. et al., ``The Safety of Newly Approved
Medicines: Do Recent Market Removals Mean There Is a Problem?''
Journal of American Medical Association, 281(18):1728-34, 1999.
7. ``Adverse Drug Events: The Magnitude of Health Risks Is
Uncertain Because of Limited Incidence Data,'' U.S. General
Accounting Office, Report No. GAO/HEHS-0021, January 2000, p. 10.
8. Thomas, E. J. et al., ``Costs of Medical Injuries in Utah and
Colorado,'' Inquiry, 36:255-64, 1999.
9. Ernst, F. R., and A. J. Grizzle, ``Drug-Related Morbidity and
Mortality: Updating the Cost-of-Illness Model,'' Journal of the
American Pharmaceutical Association, 41(2):192-199, 2001.
10. Viscusi, W. K., ``Individual Rationality, Hazard Warnings,
and the Foundations of Tort Law,'' Rutgers Law Review, 48:625-671,
1996.
11. ``Establishment and Firm Size, 1997 Economic Census, Retail
Trade,'' U.S. Department of Commerce, U.S. Census Bureau,
Publication No. EC97R44S-SZ, October 2000, pp. 135, 139, 152, 160.
12. ``Establishment and Firm Size, 1997 Economic Census, Health
Care and Social Assistance, Subject Series,'' U.S. Department of
Commerce, U.S. Census Bureau, publication EC97S62S-SZ, October 2000,
pp. 88-90, 97-103, and 106.
13. ``Pharmaceutical Preparation Manufacturing, 1997 Economic
Census, Manufacturing, Industry Series,'' U.S. Department of
Commerce, U.S. Census Bureau, Publication No. EC97M-3254B, November
1999, p. 9.
14. ``Statistics of U.S. Businesses: 1999, Pharmaceutical
Preparation Manufacturing, United States,'' U.S. Department of
Commerce, U.S. Census Bureau, http://www.census.gov/epcd/susb/1999/us/US325412.htm (last viewed September 12, 2002).
List of Subjects
21 CFR Part 201
Drugs, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 208
Labeling, Prescription drugs, Reporting and recordkeeping
requirements.
21 CFR Part 209
Authorized dispensers, Drugs, Pharmacies, Prescription drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 201 and 208 be amended and part 209 be added
as follows:
PART 201--LABELING
1. The authority citation for 21 CFR part 201 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360,
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.
2. Amend Sec. 201.66 by adding two sentences at the end of
paragraph (c)(5)(vii) to read as follows:
Sec. 201.66 Format and content requirements for over-the-counter
(OTC) drug product labeling.
* * * * *
(c) * * *
(5) * * *
(vii) * * * For all OTC drug products under an approved drug
application, the following text shall immediately follow the
subheading: ``[Bullet] side effects occur. You may report side effects
to FDA at 1-800-FDA-1088.'' The telephone number must appear in a
minimum 6-point bold letter height or type size.
* * * * *
PART 208--MEDICATION GUIDES FOR PRESCRIPTION DRUG PRODUCTS
3. The authority citation for 21 CFR part 208 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360, 371, 374; 42 U.S.C. 262.
4. Amend Sec. 208.20 by adding paragraph (b)(7)(iii) to read as
follows:
Sec. 208.20 Content and format of a Medication Guide.
* * * * *
(b) * * *
(7) * * *
(iii) For drug products approved under section 505 of the act, the
following verbatim statement: ``Call your doctor for medical advice
about side effects. You may report side effects to FDA at 1-800-FDA-
1088.''
* * * * *
5. Add part 209 to read as follows:
PART 209--REQUIREMENT FOR AUTHORIZED DISPENSERS AND PHARMACIES TO
DISTRIBUTE A SIDE EFFECTS STATEMENT
Subpart A--General Provisions
Sec.
209.1 Scope and purpose.
209.2 Definitions.
Subpart B--Requirements
209.10 Content and format of the side effects statement.
209.11 Dispensing and distributing the side effects statement.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 371; 42
U.S.C. 241.
Subpart A--General Provisions
Sec. 209.1 Scope and purpose.
(a) This part sets forth requirements for human prescription drug
products approved under section 505 of the Federal Food, Drug, and
Cosmetic Act and dispensed by authorized dispensers and pharmacies to
consumers. This part requires distribution of a side effects statement
and applies to new and refill prescriptions. This part is not intended
to apply to authorized dispensers dispensing or administering
prescription drug products to inpatients in a hospital or health care
facility under an order of a licensed practitioner, or as part of
supervised home health care.
(b) The purpose of providing the side effects statement is to
enable consumers to report side effects of prescription drug products
to FDA.
Sec. 209.2 Definitions.
For the purposes of this part, the following definitions apply:
Act means the Federal Food, Drug, and Cosmetic Act (sections 201-
907 (21 U.S.C. 301-397)).
Authorized dispenser means an individual licensed, registered, or
otherwise permitted by the jurisdiction in which the individual
practices to provide drug products on prescription in the course of
professional practice.
Consumer medication information means written information
voluntarily provided to consumers by dispensing pharmacists as part of
patient medication counseling activities.
Medication Guide means FDA-approved patient labeling conforming to
the specifications set forth in part 208 of this chapter and other
applicable regulations.
Pharmacy includes, but is not limited to, a retail, mail order,
Internet, hospital, university, or clinic pharmacy, or a public health
agency, regularly and lawfully engaged in dispensing prescription
drugs.
Side effects statement means the following verbatim statement:
``Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.''
[[Page 21794]]
Subpart B--Requirements
Sec. 209.10 Content and format of the side effects statement.
(a) Content. The side effects statement provided with each
prescription drug product approved under section 505 of the act must
read: ``Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.''
(b) Format. The side effects statement must be in a single, clear,
easy-to-read type style. The letter height or type size used for the
side effects statement in accordance with paragraphs (b)(1) and (b)(2)
of Sec. 209.11 must be no smaller than 6 points (1 point = 0.0138
inches). The letter height or type size for the side effects statement
under paragraphs (b)(3), (b)(4), and (b)(5) of Sec. 209.11 must be no
smaller than 10 points.
Sec. 209.11 Dispensing and distributing the side effects statement.
(a) Each authorized dispenser or pharmacy must distribute the side
effects statement with each prescription drug product approved under
section 505 of the act and dispensed. The side effects statement must
be distributed with new and refill prescriptions.
(b) An authorized dispenser or pharmacy must choose one or more of
the following options to distribute the side effects statement:
(1) Distribute the side effects statement on a sticker attached to
the unit package, vial, or container of the drug product;
(2) Distribute the side effects statement on a preprinted pharmacy
prescription vial cap;
(3) Distribute the side effects statement on a separate sheet of
paper;
(4) Distribute the side effects statement in consumer medication
information; or
(5) Distribute the appropriate FDA-approved Medication Guide that
contains the side effects statement.
Dated: December 30, 2004.
Mark B. McClellan,
Commissioner of Food and Drugs.
Dated: December 30, 2004.
Tommy G. Thompson,
Secretary of Health and Human Services.
Note: The following appendix will not appear in the Code of
Federal Regulations.
Appendix
IMS Health collects data on the quantity of products purchased
by retail and nonretail pharmacies. Data may be reported three ways,
by ``extended units'' (EUs), ``eaches'' (EAs), and ``units'' (UNs).
IMS defines ``extended units'' as the individual tablet or capsule
for solid dosage forms and the weight or volume (i.e., grams or
milliliters) for other dosage forms, ``eaches'' as individual
product packages (e.g., a vial, bottle or packet of pills), and
``units'' as individual shipping packages. None of these definitions
correlates directly to the number of prescriptions dispensed.
However, comparing retail prescription volume to the number of
products purchased by the sector provides a rough estimate of the
average number of EUs, EAs or UNs per prescription. Applying these
three averages to the number of drug products purchased by the
nonretail pharmacy sector yields rough estimates of the number of
prescriptions dispensed by these outlets. Although uncertain, the
range of prescriptions derived by this method is used to estimate
the impact of the proposed rule on the nonretail pharmacy sector.
These estimates were derived by FDA using IMS data. Although they
were reviewed by IMS, they do not necessarily represent IMS views.
The agency requests comments from nonretail outlets on its
derivation of prescription volume.
The number of prescriptions dispensed, and the number of UNs,
EAs and EUs purchased for different types of retail pharmacies are
shown in Table A-1 of this appendix. In addition, the average number
of products purchased per prescription dispensed is calculated for
each of the three definitions of purchased products.
Table A-1.--Number of Prescription Drugs Dispensed, Number of Pharmaceutical Products Purchased, and Average
Number of Pharmaceutical Products per Prescription in 2001 by Retail Channel
----------------------------------------------------------------------------------------------------------------
No. of No. of Products Purchased Average No. of Products Purchased
Prescriptions (million) per Prescription Dispensed\1\
Retail Channel Dispensed -----------------------------------------------------------------------
(million) UNs EAs EUs UNs EAs EUs
----------------------------------------------------------------------------------------------------------------
Mail Order 163.51 275.47 459.75 24,451.36 1.68 2.81 149.54
----------------------------------------------------------------------------------------------------------------
Independents 778.68 519.59 860.84 67,534.84 0.67 1.11 86.73
----------------------------------------------------------------------------------------------------------------
Food Stores 426.52 755.80 1,031.86 156,898.89 1.77 2.42 367.86
----------------------------------------------------------------------------------------------------------------
Chain Stores\2\ 1,715.60 2,159.40 3,089.18 265,991.78 1.26 1.80 155.04
----------------------------------------------------------------------------------------------------------------
Sources: IMS Health, National Prescription Audit Plus, Year 2001, data extracted June 2002; IMS Health, Retail
Perspective, Year 2001, data extracted June 2002.
\1\ Averages equal the number of UNs, EAs or EUs, divided by the number of prescriptions.
\2\ Includes traditional chain stores and mass merchants.
Table A-2 of this appendix displays IMS data for the number of
UNs, EAs and EUs shipped to each nonretail channel with outpatient
services. Data for clinics and HMOs may include drugs administered
to inpatients of these facilities. For this analysis, the agency
conservatively assumes that clinics and HMOs dispense all their
products to outpatients. Similar to clinics and HMOs, hospital data
include pharmaceutical products purchased for both outpatient and
inpatient use. Unlike the other health care facilities listed,
hospitals administer most drugs to inpatients. Thus the data for
hospitals are adjusted by the share of revenue from outpatient
services reported in the 1997 Economic Census (Ref. 3).
Although most nonretail channels defined by IMS Health agree
closely with NAICS codes, according to Census data, 9,720 offices of
health care practitioners reported revenue from pharmaceutical
products in 1997. Because the number of products purchased by these
offices is minor compared to other nonretail channels, they are not
reported separately in the IMS data and would be included with data
on other miscellaneous outlets. Therefore, for this analysis, other
miscellaneous outlets are considered equivalent to offices of health
care practitioners.
[[Page 21795]]
Table A-2.--Number of Pharmaceutical Products Purchased by Nonretail Channels in 2001\1\
----------------------------------------------------------------------------------------------------------------
No. Purchased by Quantity Measure (million)
Nonretail Channel -----------------------------------------------------------------
UNs EAs EUs
----------------------------------------------------------------------------------------------------------------
Miscellaneous other, excluding prisons and 9.86 16.26 1,422.93
universities
----------------------------------------------------------------------------------------------------------------
Clinics, including universities 121.78 342.24 10,444.36
----------------------------------------------------------------------------------------------------------------
HMOs 26.79 44.87 2,764.78
----------------------------------------------------------------------------------------------------------------
Federal and non-Federal hospitals 446.09 2,112.93 81,395.52
----------------------------------------------------------------------------------------------------------------
Hospitals adjusted by share of revenue from 118.11 559.46 21,551.76
outpatient services\2\
----------------------------------------------------------------------------------------------------------------
\1\ Source: IMS Health, Provider Perspective, Year 2001, data extracted June 2002.
\2\ The weighted average share of revenue from outpatient services for NAICS 622 equals 26.5% (Ref. 3).
Three weighted averages were calculated based on the retail
sector data in Table A-1 of this appendix and vary from 1.20 UNs per
prescription to 166.93 EU per prescription (see Table A-3 of this
appendix). To derive an estimate of the number of prescriptions
dispensed by nonretail channels, the weighted average number of
products per prescription shown in Table A-3 of this appendix is
applied to the nonretail sector purchase data. This yields estimates
that range from approximately 217 million to 546 million
prescriptions per year (Table A-4 of this appendix).
Table A-3.--Per Prescription Weighted Average by Quantity Type and Retail Channel\1\
----------------------------------------------------------------------------------------------------------------
Weighted Average No. Per Prescription by
Share of Dispensed Quantity Type
Retail Channel Prescriptions -----------------------------------------------
UNs EAs EUs
----------------------------------------------------------------------------------------------------------------
Mail Order 5% 0.09 0.15 7.93
----------------------------------------------------------------------------------------------------------------
Independents 25% 0.17 0.28 21.90
----------------------------------------------------------------------------------------------------------------
Food Stores 14% 0.25 0.33 50.87
----------------------------------------------------------------------------------------------------------------
Chain Stores\2\ 56% 0.70 1.00 86.24
----------------------------------------------------------------------------------------------------------------
Total Weighted Average 100% 1.20 1.76 166.93
----------------------------------------------------------------------------------------------------------------
Sources: IMS Health, National Prescription Audit Plus, Year 2001, data extracted June 2002, IMS Health, Retail
Perspective, Year 2001, data extracted June 2002.
\1\ Each channel's weighted average equals the share of retail prescriptions for the channel, multiplied by the
corresponding average in Table A-1. The total weighted average for UNs, EAs, or EUs is the sum of the
individual channel's weighted average in the column. Totals may not sum or multiply due to rounding.
\2\ Includes traditional chain stores and mass merchants.
Table A-4.--Estimated Number of Outpatient Prescriptions Dispensed by Nonretail Channels
----------------------------------------------------------------------------------------------------------------
Estimated No. of Outpatient Prescriptions Dispensed (millions)
Nonretail Channel by NAICS ------------------------------------------------------------------------------------
Code Based on UNs\1\ Based on EAs\1\ Based on EUs\1\
----------------------------------------------------------------------------------------------------------------
NAICS 6211, 6212 and 6213: 8.2 9.2 8.5
Offices of Health Care
Practitioners\2\
----------------------------------------------------------------------------------------------------------------
NAICS 6214, except NAICS 101.2 194.0 62.6
621491: Outpatient Care
Centers, except HMOs\3\
----------------------------------------------------------------------------------------------------------------
NAICS 621491: HMO Medical 22.3 25.4 16.6
Centers\4\
----------------------------------------------------------------------------------------------------------------
NAICS 622: Hospital 98.2 317.1 129.1
Outpatient Services\5\
----------------------------------------------------------------------------------------------------------------
Total 229.9 545.7 216.8
----------------------------------------------------------------------------------------------------------------
Sources: IMS Health, National Prescription Audit Plus, Year 2001, data extracted June 2002; IMS Health, Provider
Perspective, Year 2001, data extracted June 2002; IMS Health, Retail Perspective, Year 2001, data extracted
June 2002.
\1\ Weighted average quantity/script from Table A-3: UNs/Prescription = 1.20, EAs/Prescription = 1.76, EUs/
Prescription = 166.93.
\2\ Corresponds to IMS data for miscellaneous-other, excluding prisons and universities.
\3\ Corresponds to IMS data for clinics including miscellaneous-universities.
\4\ Corresponds to IMS data for HMOs.
\5\ Corresponds to IMS data for Federal and non-Federal hospitals adjusted for share of revenue from outpatient
services.
[[Page 21796]]
[FR Doc. 04-9069 Filed 4-21-04; 8:45 am]
BILLING CODE 4160-01-S