[Federal Register Volume 64, Number 220 (Tuesday, November 16, 1999)]
[Rules and Regulations]
[Pages 62110-62112]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-29854]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 99N-0188]


Progestational Drug Products for Human Use; Requirements for 
Labeling Directed to the Patient

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is revoking its 
regulation requiring patient labeling for progestational drug products. 
Patient labeling had been required to inform patients of an increased 
risk of birth defects reported to be associated with the use of these 
drugs during the first 4 months of pregnancy. FDA concluded that, based 
on a review of the scientific data, such labeling for all progestogens 
is not warranted. In addition, the diversity of drugs that can be 
described as progestational and the diversity of conditions these drugs 
may be used to treat make it inappropriate to consider these drugs a 
single class for labeling purposes. This action is intended to provide 
consumers with more

[[Page 62111]]

appropriate labeling for certain drug products.

EFFECTIVE DATE: November 16, 2000.

FOR FURTHER INFORMATION CONTACT: Diane V. Moore, Center for Drug 
Evaluation and Research (HFD-580), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-4260.

SUPPLEMENTARY INFORMATION:

 I. Background

     In the 1970's, there were several reports suggesting ``an 
association between intrauterine exposure to sex hormone treatment and 
congenital anomalies, including congenital heart defects and limb 
reduction defects'' (42 FR 37646, July 22, 1977). Based on these 
reports, FDA published a proposed rule to require patient labeling for 
progestational drug products (42 FR 37643, July 22, 1977). The category 
``progestational drug products'' included natural progesterone and all 
synthetic progestins. The regulation was finalized on October 13, 1978 
(43 FR 47178), and was codified at Sec. 310.516 (21 CFR 310.516). It 
required that progestational drug products be dispensed with a patient 
package insert containing a ``brief discussion of the nature of the 
risks of birth defects resulting from the use of these drugs during the 
first 4 months of pregnancy'' (Sec. 310.516(b)(4)). The regulation 
applied to any drug product that contains a progestogen, with the 
exceptions of contraceptives and oral dosage forms labeled solely for 
the treatment of advanced cancer\1\ (310.516(e)(4)).
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    \1\  The original regulation exempted contraceptives, which were 
required to comply with the labeling requirements of 21 CFR 310.501. 
In 1981, the regulation was amended to exempt advanced cancer drugs 
(46 53656, October 30, 1981).
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 II. The Final Rule

     In the Federal Register of April 13, 1999 (64 FR 17985), FDA 
published a proposed rule to revoke its regulation requiring patient 
labeling for progestational drug products. FDA concluded that, based on 
a review of the scientific data, such labeling for all progestogens is 
not warranted. In addition, the diversity of drugs that can be 
described as progestational and the diversity of conditions these drugs 
may be used to treat make it inappropriate to consider these drugs a 
single class for labeling purposes. For more detailed descriptions of 
the scientific basis for revoking the rule and the history of the 
rule's adoption, see the proposed rule (64 FR 17985).
     FDA received only three comments on the proposed rule, two from 
university professors and one from a trade association of pharmacists. 
Two comments commended FDA's action. The third comment stated that each 
individual progestational drug product should carry warnings 
appropriate to that particular product and that a teratogenic warning 
might be appropriate for a particular progestin. FDA agrees and will 
require labeling that is appropriate to the dose and indication of each 
progestational drug product. Thus, FDA is adopting the rule as 
proposed.

 III. Guidance Texts

     In 1977, when FDA proposed the rule concerning progestational drug 
products, it published guidance texts for physician and patient 
labeling warning of possible heart and limb defects (42 FR 37647 and 
37648, July 22, 1977). FDA revised these guidance texts in the Federal 
Register of January 12, 1989 (54 FR 1243). The revised texts deleted 
the warning about possible congenital heart defects and limb reduction 
defects and added a warning about an increased risk of certain genital 
abnormalities. Concurrently with the 1999 proposed rule to revoke 
Sec. 310.516, FDA published a notice announcing that it intended to 
revoke the guidance texts for physician and patient labeling (64 FR 
18035, April 13, 1999). FDA received no comments concerning the 
revocation of the guidance texts. Elsewhere in this issue of the 
Federal Register, FDA is publishing a notice revoking those guidance 
texts.

 IV. Analysis of Impacts

     FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act (Public Law 104-4). Executive Order 12866 
directs agencies to assess all costs and benefits of available 
regulatory 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, unless an agency certifies that a rule will not have a 
significant impact on small entities, the agency must analyze 
regulatory options that would minimize the impact of the rule on small 
entities. The Unfunded Mandates Reform Act (in section 202) requires 
that agencies prepare an assessment of anticipated costs and benefits 
before proposing any rule that may result in an expenditure in any 1 
year by State, local, and tribal governments, in the aggregate, or by 
the private sector, of $100 million or more (adjusted annually for 
inflation).
     The agency has reviewed this final rule and has determined that it 
is consistent with the regulatory philosophy and principles identified 
in Executive Order 12866 and these two statutes. With respect to the 
Regulatory Flexibility Act, the agency certifies that the rule will not 
have a significant effect on a substantial number of small entities. 
Because the final rule does not impose any mandates on State, local, or 
tribal governments or the private sector that will result in a 1-year 
expenditure of $100 million or more, FDA is not required to perform a 
cost-benefit analysis under the Unfunded Mandates Reform Act. FDA 
received no comments on the proposed Analysis of Impacts.
     The final rule removes the requirement that sponsors include 
certain information in the professional labeling of affected drug 
products. The revised labeling may be filed in the next annual report. 
The agency has identified 13 sponsors and 16 distinct professional 
labeling inserts that will need to be changed to comply with this rule. 
Any professional skills necessary for implementation of this rule 
should already exist within the sponsor's firm and should not need to 
be newly acquired. Using a pharmaceutical labeling cost model developed 
for the agency by its contractor, Eastern Research Group, Inc., the 
average cost for this labeling change is $1,317 per insert, assuming a 
compliance period of 1 year. Applying this cost to the 16 professional 
labeling inserts results in a one-time cost of compliance of $21,000. 
There will also be an additional minor cost of lost inventory. Of the 
13 sponsors affected, fewer than 5 would meet the Small Business 
Administration's definition of a small entity. No additional burdens 
are imposed upon manufacturers. Therefore, in accordance with the 
Regulatory Flexibility Act, FDA certifies that this rule will not have 
a significant economic impact on a substantial number of small 
entities.

 V. Paperwork Reduction Act of 1995

     FDA concludes that this final rule contains no collections of 
information. The final rule removes the requirement that certain 
information be included in the labeling of affected drug products. The 
revised labeling may be filed in the next annual report, which is 
already required under FDA regulations and is already approved by the 
Office of Management and Budget (OMB) as a collection of information 
(OMB control no. 0910-0001). Therefore, clearance by

[[Page 62112]]

OMB under the Paperwork Reduction Act of 1995 is not required.

 VI. Environmental Impact

     The agency has determined under 21 CFR 25.30(h) that this action 
is of a class of actions 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.

 VII. Effective Date

     This final rule becomes effective 1 year after its date of 
publication in the Federal Register.

 List of Subjects in 21 CFR Part 310

     Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.
     Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under the authority delegated to the 
Commissioner of Food and Drugs, 21 CFR part 310 is amended as follows:

 PART 310--NEW DRUGS

     1. The authority citation for 21 CFR part 310 continues to read as 
follows:

     Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 
263b-263n.


Sec. 310.516   [Removed]

     2. Section 310.516 Progestational drug products; labeling directed 
to the patient is removed.

    Dated: November 4, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-29854 Filed 11-15-99; 8:45 am]
BILLING CODE 4160-01-F