[Federal Register: March 8, 1999 (Volume 64, Number 44)]
[Rules and Regulations]
[Page 10944-10947]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08mr99-12]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 216
[Docket No. 98N-0655]
List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations to include a list of drug products that may not be used for
pharmacy compounding under the exemptions under section 503A of the
Federal Food, Drug, and Cosmetic Act (the act) because they have had
their approval withdrawn or were removed from the market because the
drug product or its components have been found to be unsafe or not
effective. The list has been compiled under the new statutory
requirements of the Food and Drug Administration Modernization Act of
1997 (Modernization Act).
DATES: This rule is effective on April 7, 1999.
FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 5600
Fishers
[[Page 10945]]
Lane, Rockville, MD 20857, 301-594-2041.
SUPPLEMENTARY INFORMATION:
I. Background
Section 127 of the Modernization Act (Pub. L. 105-115), which
added section 503A to the act (21 U.S.C. 353a), describes the
circumstances under which compounded drugs qualify for exemptions from
certain adulteration, misbranding, and new drug provisions of the act
(i.e., 501(a)(2)(B), 502(f)(1), and 505 of the act (21 U.S.C.
351(a)(2)(B), 352(f)(1), and 355)).
Section 503A of the act contains several conditions that must be
satisfied for pharmacy compounding to qualify for the exemptions.
Section 503A(b)(1)(C) of the act provides that the licensed pharmacist
or licensed physician does not ``compound a drug product that appears
on a list published by the Secretary in the Federal Register of drug
products that have been withdrawn or removed from the market because
such drug products or components of such drug products have been found
to be unsafe or not effective.'' Section 503A(d)(1) of the act requires
that the list of drug products that have been withdrawn or removed from
the market because they were unsafe or not effective be issued as a
regulation and that an advisory committee be consulted in the
rulemaking process.
In the Federal Register of October 8, 1998 (63 FR 54082), FDA
proposed a rule to establish the list of drug products that have been
withdrawn or removed from the market because they were unsafe or not
effective. The primary focus of that initial proposed rule and this
final rule is on drug products that have been withdrawn or removed from
the market because they were found to be unsafe. FDA may initiate
rulemaking to add other drug products to the list that have been
withdrawn or removed from the market because they were found to be not
effective or to update the list as new information becomes available to
the agency regarding products that were removed from the market because
they were unsafe. The proposed rule was presented to the Pharmacy
Compounding Advisory Committee at a meeting held on October 14 and 15,
1998 (see the Federal Register of September 4, 1998 (63 FR 47301)). The
committee did not have any adverse comments on the proposed rule and
did not suggest any changes.
II. Comments on the Proposed Rule
FDA received comments from consumers, pharmacists, a medical
doctor, a pharmaceutical manufacturer, a pharmaceutical manufacturers'
organization, and a committee representing the plaintiffs in a drug
product liability class action suit.
1. Two comments questioned FDA's shortening the comment period
from 75 to 45 days.
As FDA stated in the preamble to the proposed rule (63 FR 54082 at
54087 to 54088), the agency believes that a shorter comment period was
warranted to expedite this rulemaking proceeding because the
compounding of many of the drug products on the list would present a
serious threat to the public health. Many of the drug products have
caused death or life-threatening conditions. Some of the drugs on the
list are believed to cause cancer, while others were shown to be toxic
to the liver and other organs.
2. One comment objected to the wording of the first sentence of
proposed Sec. 216.24, which says ``The following drug products were
withdrawn or removed from the market because such drug products or
components of such drug products were found to be unsafe or not
effective.'' The comment expressed concerns that the finding that a
drug was withdrawn from the market by the manufacturer because it was
not safe or effective might be used in a product liability lawsuit
against the manufacturer who voluntarily withdrew the drug product from
the market. The comment also expressed concerns that fear of having the
finding used against them might discourage manufacturers from
voluntarily withdrawing drug products when concerns about the drug
product's safety and effectiveness have developed.
The agency does not believe it is necessary to change the wording
of Sec. 216.24 in response to this comment. Compounding pharmacists and
physicians are the intended audience for this rule. The purpose of
Sec. 216.24 is to provide these compounders a list of drugs that they
may not compound under section 503A of the act. This list is not
intended to be used as evidence in a product liability suit, and the
addition of language designed to minimize the potential effect of the
list in litigation is unnecessary to fulfill its intended purpose.
For the purposes of this rule, FDA has determined that it is not
necessary to deviate from the statutory language found in section
503A(b)(1)(C) of the act, which prohibits compounders from compounding
``a drug product that appears on a list published by [FDA] in the
Federal Register of drug products that have been withdrawn or removed
from the market because such drug products or components of such drug
products have been found to be unsafe or ineffective.''
The agency wishes to emphasize that the inclusion of a drug
product on the list does not mean that the drug product was marketed
negligently, was defective, or was marketed in breach of any warranty.
Even after exhaustive clinical studies, safety problems may not become
apparent until a drug product has been in commercial distribution for a
significant amount of time, so the fact that a drug was removed or
withdrawn from the market does not mean that the drug was improperly
placed in commercial distribution.
3. A large number of comments objected to drug products containing
adrenal cortex being placed on the list. One of the comments included a
photocopy of an article from the November issue of the magazine
Nutrition & Healing. This article apparently is the source of much of
the content of many of the comments. None of the comments provided any
information about the removal of adrenal cortex extract from the
market, other than the unsupported statements that the removal of
adrenal cortex extract was economically motivated. These comments
included unsupported statements that adrenal cortex extract has never
been associated with a death or serious adverse event (except for a
series of adverse events in 1996 and 1997 associated with contaminated
adrenal cortex extract) and that adrenal cortex extract is safer and
more effective than the synthetic adrenocortical steroids that have
replaced it in medical use. The comments also asserted, without
presenting any scientific data or historical information to support the
assertion, that FDA acted improperly in directing the removal of drugs
containing adrenal cortex from the market because the low levels of
corticosteroids found in the drugs presented a substantial risk of
undertreatment of serious conditions.
FDA's concerns about the safety of adrenal cortex extract have
grown stronger since the drug product was removed from the market in
1978. Adrenal cortex extract is derived from the cortex adrenal glands
of domestic food animals, including cattle. In 1986 the disease bovine
spongiform encephalopathy (BSE) was identified in cattle. BSE has been
found to be epidemic in Great Britain and present in Western Europe and
Oman. Hundreds of thousands of cattle have either died or been
destroyed as a result of BSE infection. Since that time strong evidence
has been developed associating ingestion of tissues from
[[Page 10946]]
BSE-infected cattle with the development of new variant Creutzfeldt-
Jakob disease (nvCJD) in humans. A patient taking a drug derived from
the adrenal cortex of a BSE-infected cow would be running an
unacceptable risk of contracting nvCJD. Due to the destruction of BSE-
infected cattle and other controls (see the Federal Register of August
29, 1994 (59 FR 44591)), the chances of a patient getting nvCJD from
adrenal cortex extract are low. However, there is still a risk involved
in taking adrenal cortex extract, and that risk must be taken very
seriously in light of the fact that nvCJD appears to always be fatal.
Concerning the comments that FDA acted improperly in removing
drugs containing adrenal cortex from the market because of a
substantial risk of undertreatment of serious conditions, FDA's action
was investigated by the General Accounting Office and found to be
proper (see ``By the Comptroller General, Report to the Honorable Barry
M. Goldwater, Jr., House of Representatives of the United States:
Adrenal Cortical Extract Taken Off Drug Market'' (HRD-81-61, 1981)).
For the reasons stated previously, FDA is keeping drug products
containing adrenal cortex on the list of drugs that may not be
compounded under section 503A of the act.
4. One comment strongly supported the inclusion of drug products
containing dexfenfluramine hydrochloride and fenfluramine hydrochloride
on the list.
5. One comment pointed out that there is a hearing request pending
before the agency regarding the withdrawal of approval of the
applications for neomycin sulfate in sterile vials for injection (see
the Federal Register of December 6, 1988 (53 FR 49232)) and another
pending request for a hearing regarding the withdrawal of approval of
the applications for neomycin sulfate for prescription compounding (see
the Federal Register of December 6, 1988 (53 FR 49231)). A petition for
stay of action regarding the two actions mentioned above and regarding
a labeling guideline for neomycin sulfate for prescription compounding
(see the Federal Register of April 15, 1988 (53 FR 12662)) is also
pending before the agency.
Because of the complex administrative record on neomycin sulfate
currently before the agency and because of the public health need to
expedite implementation of this rule, FDA is postponing final action on
listing all parenteral drug products containing neomycin sulfate.
Parenteral drug products containing neomycin sulfate may be added to
the list at a later date.
III. Environmental Impact
The agency 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.
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 of 1995 (Pub. L. 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). Executive Order 12866
classifies a rule as significant if it meets any one of a number of
specified conditions, including having an annual effect on the economy
of $100 million or adversely affecting in a material way a sector of
the economy, competition, or jobs, or if it raises novel legal or
policy issues. As discussed in the paragraphs below, the agency
believes that this rule is consistent with the regulatory philosophy
and principles identified in the Executive Order. In addition, the
final rule is not a significant regulatory action as defined by the
Executive Order and so is not subject to review under the Executive
Order.
The agency has not estimated any compliance costs or loss of sales
due to this final rule because it prohibits pharmacy compounding of
only those drug products that have already been withdrawn or removed
from the market. The agency is not aware of any routine use of these
drug products in pharmacy compounding and received no significant data
in response to the request in the preamble to the proposed rule for the
submission of comments on this issue and current compounding usage data
for these drug products. Additionally, FDA did not receive any comments
on compliance costs and loss of sales due to this rule or current
compounding usage data for the drug products listed in this rule at the
Pharmacy Compounding Advisory Committee meeting held on October 14 and
15, 1998.
Unless an agency certifies that a rule will not have a significant
economic impact on a substantial number of small entities, the
Regulatory Flexibility Act requires agencies to analyze regulatory
options to minimize any significant economic impact of a regulation on
small entities. The agency is taking this action in order to comply
with section 503A of the act. This provision specifically directs the
FDA to develop a list of drug products that have been withdrawn or
removed from the market because such products or components have been
found to be unsafe or not effective. Any drug product on this list will
not qualify for the pharmacy compounding exemptions under section 503A
of the act. The drug products on this list were manufactured by many
different pharmaceutical firms, some of which may have qualified under
the Small Business Administration (SBA) regulations (those with less
than 750 employees) as small businesses. However, since the list only
includes those drug products that have already been withdrawn or
removed from the market for safety or efficacy concerns, this final
rule will not negatively impact these small businesses. Moreover, no
compliance costs are estimated for any of these small pharmaceutical
firms because they are not the subject of this rule and are not
expected to realize any loss of sales due to this rule. Further, the
SBA guidelines limit the definition of small drug stores or pharmacies
to those that have less than $5.0 million in sales. Again, the
pharmacies that qualify as small businesses are not expected to incur
any compliance costs or loss of sales due to this regulation because
the products have already been withdrawn or removed from the market,
and the agency believes that these drugs would be compounded only very
rarely, if ever. Therefore, FDA certifies that this rule will not have
a significant economic impact on a substantial number of small
entities.
Section 202 of the Unfunded Mandates Reform Act requires that
agencies prepare an assessment of anticipated costs and benefits before
it finalizes any rule requiring any expenditure by State, local, and
tribal governments, in the aggregate, or by the private sector of $100
million (adjusted annually for inflation) in any 1 year. The
publication of the list of products withdrawn or removed from the
market because they were found to be unsafe or ineffective will not
result in expenditures of funds by State, local, and tribal governments
or the private sector in excess of $100 million annually. Because the
agency does not estimate any annual expenditures due to the final rule,
FDA is not required to
[[Page 10947]]
perform a cost/benefit analysis according to the Unfunded Mandates
Reform Act.
V. Paperwork Reduction Act of 1995
This final rule contains no collection of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
List of Subjects in 21 CFR Part 216
Drugs, Pharmacy compounding, Prescription drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and
under authority delegated to the Commissioner of Food and Drugs, 21 CFR
part 216 is added to read as follows:
PART 216--PHARMACY COMPOUNDING
Subpart A--General Provisions [Reserved]
Subpart B--Compounded Drug Products
Sec.
216.23 [Reserved]
216.24 Drug products withdrawn or removed from the market for
reasons of safety or effectiveness.
Authority: 21 U.S.C. 351, 352, 353a, 355, and 371.
Subpart A--General Provisions [Reserved]
Subpart B--Compounded Drug Products
Sec. 216.23 [Reserved]
Sec. 216.24 Drug products withdrawn or removed from the market for
reasons of safety or effectiveness.
The following drug products were withdrawn or removed from the
market because such drug products or components of such drug products
were found to be unsafe or not effective. The following drug products
may not be compounded under the exemptions provided by section 503A(a)
of the Federal Food, Drug, and Cosmetic Act:
Adenosine phosphate: All drug products containing adenosine
phosphate.
Adrenal cortex: All drug products containing adrenal cortex.
Azaribine: All drug products containing azaribine.
Benoxaprofen: All drug products containing benoxaprofen.
Bithionol: All drug products containing bithionol.
Bromfenac sodium: All drug products containing bromfenac sodium.
Butamben: All parenteral drug products containing butamben.
Camphorated oil: All drug products containing camphorated oil.
Carbetapentane citrate: All oral gel drug products containing
carbetapentane citrate.
Casein, iodinated: All drug products containing iodinated
casein.
Chlorhexidine gluconate: All tinctures of chlorhexidine
gluconate formulated for use as a patient preoperative skin
preparation.
Chlormadinone acetate: All drug products containing
chlormadinone acetate.
Chloroform: All drug products containing chloroform.
Cobalt: All drug products containing cobalt salts (except
radioactive forms of cobalt and its salts and cobalamin and its
derivatives).
Dexfenfluramine hydrochloride: All drug products containing
dexfenfluramine hydrochloride.
Diamthazole dihydrochloride: All drug products containing
diamthazole dihydrochloride.
Dibromsalan: All drug products containing dibromsalan.
Diethylstilbestrol: All oral and parenteral drug products
containing 25 milligrams or more of diethylstilbestrol per unit
dose.
Dihydrostreptomycin sulfate: All drug products containing
dihydrostreptomycin sulfate.
Dipyrone: All drug products containing dipyrone.
Encainide hydrochloride: All drug products containing encainide
hydrochloride.
Fenfluramine hydrochloride: All drug products containing
fenfluramine hydrochloride.
Flosequinan: All drug products containing flosequinan.
Gelatin: All intravenous drug products containing gelatin.
Glycerol, iodinated: All drug products containing iodinated
glycerol.
Gonadotropin, chorionic: All drug products containing chorionic
gonadotropins of animal origin.
Mepazine: All drug products containing mepazine hydrochloride or
mepazine acetate.
Metabromsalan: All drug products containing metabromsalan.
Methamphetamine hydrochloride: All parenteral drug products
containing methamphetamine hydrochloride.
Methapyrilene: All drug products containing methapyrilene.
Methopholine: All drug products containing methopholine.
Mibefradil dihydrochloride: All drug products containing
mibefradil dihydrochloride.
Nitrofurazone: All drug products containing nitrofurazone
(except topical drug products formulated for dermatalogic
application).
Nomifensine maleate: All drug products containing nomifensine
maleate.
Oxyphenisatin: All drug products containing oxyphenisatin.
Oxyphenisatin acetate: All drug products containing
oxyphenisatin acetate.
Phenacetin: All drug products containing phenacetin.
Phenformin hydrochloride: All drug products containing
phenformin hydrochloride.
Pipamazine: All drug products containing pipamazine.
Potassium arsenite: All drug products containing potassium
arsenite.
Potassium chloride: All solid oral dosage form drug products
containing potassium chloride that supply 100 milligrams or more of
potassium per dosage unit (except for controlled-release dosage
forms and those products formulated for preparation of solution
prior to ingestion).
Povidone: All intravenous drug products containing povidone.
Reserpine: All oral dosage form drug products containing more
than 1 milligram of reserpine.
Sparteine sulfate: All drug products containing sparteine
sulfate.
Sulfadimethoxine: All drug products containing sulfadimethoxine.
Sulfathiazole: All drug products containing sulfathiazole
(except those formulated for vaginal use).
Suprofen: All drug products containing suprofen (except
ophthalmic solutions).
Sweet spirits of nitre: All drug products containing sweet
spirits of nitre.
Temafloxacin hydrochloride: All drug products containing
temafloxacin.
Terfenadine: All drug products containing terfenadine.
3,3',4',5-tetrachlorosalicylanilide: All drug products
containing 3,3',4',5-tetrachlorosalicylanilide.
Tetracycline: All liquid oral drug products formulated for
pediatric use containing tetracycline in a concentration greater
than 25 milligrams/milliliter.
Ticrynafen: All drug products containing ticrynafen.
Tribromsalan: All drug products containing tribromsalan.
Trichloroethane: All aerosol drug products intended for
inhalation containing trichloroethane.
Urethane: All drug products containing urethane.
Vinyl chloride: All aerosol drug products containing vinyl
chloride.
Zirconium: All aerosol drug products containing zirconium.
Zomepirac sodium: All drug products containing zomepirac sodium.
Dated: March 1, 1999.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 99-5517 Filed 3-5-99; 8:45 am]
BILLING CODE 4160-01-F