[Federal Register: October 15, 1996 (Volume 61, Number 200)]
[Proposed Rules]
[Page 53685-53688]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr15oc96-31]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 310
[Docket No. 96N-0144]
Over-the-Counter Drug Products Containing Colloidal Silver
Ingredients or Silver Salts
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to
establish that all over-the-counter (OTC) drug products containing
colloidal silver ingredients or silver salts for internal or external
use are not generally recognized as safe and effective and are
misbranded. FDA is issuing this proposal because many products
containing colloidal silver ingredients or silver salts are being
marketed for numerous serious disease conditions and FDA is not aware
of any substantial scientific evidence that supports the use of OTC
colloidal silver ingredients or silver salts for these disease
conditions.
DATES: Written comments by January 13, 1997; written comments on the
agency's economic impact determination by January 13, 1997. FDA is
proposing that any final rule that may issue based on this proposal
become effective 30 days after its date of publication in the Federal
Register.
ADDRESSEES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Bradford W. Williams, Center for Drug
Evaluation and Research (HFD-310), Food and Drug Administration, 7520
Standish Pl., Rockville, MD 20855, 301-594-0063.
SUPPLEMENTARY INFORMATION:
I. Background
Colloidal silver is a suspension of silver particles in a colloidal
base. Historically, a number of colloidal silver/silver colloidal salts
have been marketed in the United States. Some of these colloidal silver
products were recognized as official articles in the United States
Pharmacopeia (U.S.P.) and the National Formulary (N.F.). Colloidal
silver iodide (Ref. 1) contained not less than 18 percent and not more
than 22 percent silver, with the product diluted for local use to
concentrations from 0.05 to 10 percent. Strong silver protein (Ref. 1)
contained not less than 7.5 percent and not more than 8.5 percent
silver, with the product diluted for local use to concentrations from
0.5 to 10 percent. The 10th edition of the N.F. had a cautionary note
for these products that stated: ``Caution: Solutions of Colloidal
Silver Iodide should be freshly prepared and should be dispensed in
amber-colored bottles,'' and ``Caution: Strong Silver Protein Solutions
should be freshly prepared and should be dispensed in amber-colored
bottles.''
Mild silver protein (Ref. 2) contained not less than 19 percent and
not more than 23 percent silver, with the product diluted for local use
to concentrations from 0.1 to 5 percent. The 12th edition of the N.F.
had a cautionary note, which stated: ``Caution: Solutions of Mild
Silver Protein should be freshly prepared or contain a suitable
stabilizer, and should be dispensed in amber-colored bottles.''
Ammoniacal silver nitrate solution (Ref. 2) contained 28.5 to 30.5
percent silver, was made extemporaneously, and was used locally without
dilution. Silver nitrate solution (Ref. 3) was made extemporaneously
and was used locally at strengths from 0.1 to 10 percent.
None of these formerly recognized colloidal silver preparations has
been official in the U.S.P. or the N.F. since 1975. Moreover, of the
silver salts evaluated as part of the agency's OTC drug review thus
far, none was found to be generally recognized as safe and effective
for its intended use(s). These included silver nitrate as an astringent
(58 FR 27636, May 10, 1993) and as a smoking deterrent (58 FR 31236,
June 1, 1993) and mild silver protein as an ophthalmic anti-infective
(57 FR 60416, December 18, 1992). Silver acetate was also evaluated as
a smoking deterrent and found not to be generally recognized as safe
and effective (58 FR 31236).
II. Recent Developments
In recent years, colloidal silver preparations of unknown
formulation have been appearing in retail outlets. These products are
labeled for numerous disease conditions, including human
immunodeficiency virus (HIV), acquired immune deficiency syndrome
(AIDS), cancer, tuberculosis, malaria, lupus, syphilis, scarlet fever,
shingles, herpes, pneumonia, typhoid, exanthematic typhus, tetanus,
variola, scarlatina, erysipelas, rheumatism, candida, staphylococcus
and streptococcus infections, tonsillitis, parasites, fungus, bubonic
plague, cholera, chronic fatigue, acne, warts, Meniere's disease
(syndrome), whooping cough, enlarged prostate, perineal eczema,
hemorrhoids, impetigo, ringworm, recurrent boils, burns, and
appendicitis.
Several marketers of these products use a labeling brochure that
refers to colloidal silver as a treatment or cure for 650 diseases
(Ref. 4). Some colloidal silver products have been promoted using
reprints of articles, taken from magazines and newspapers, that make
claims of extensive health benefits for colloidal silver, similar to
the claims listed above. The articles have also been shipped with
colloidal silver products, when the products were ordered through the
mail (Ref. 5). The dosage form of these colloidal silver products is
usually oral, but product labeling also contains directions for topical
and, occasionally, intravenous use.
In October 1994, FDA issued Health Fraud Bulletin #19 (Ref. 6) to
address the emerging marketing of colloidal silver products offered for
serious disease conditions. In that bulletin, the agency stated that it
was ``not aware of any substantial scientific evidence which
demonstrates that any OTC colloidal silver solution is useful to
prevent or treat any serious disease condition.'' The bulletin
explained that FDA has not approved a new drug application (NDA) for a
colloidal silver product. In addition, the bulletin stated no data or
information has been submitted to FDA to document an exemption from the
new drug provisions of the Federal Food, Drug, and Cosmetic Act (the
act) under the 1938 or 1962 grandfather provisions. The bulletin
referred to 21 CFR 314.200(e)(2), which sets forth the type of evidence
necessary to support an exemption under a grandfather provision.
III. The ``Grandfather'' Exemption
Some marketers of various colloidal silver preparations claim their
products are exempt from the ``new drug'' provisions of section 201(p)
of the act (21 U.S.C. 321(p)) under the ``grandfather'' provisions of
the 1938 act and the 1962 amendments to the act. The marketers
frequently claim that their products were marketed before 1938, that
only insubstantial changes have been made in product formulation and
labeling since that time, and that
[[Page 53686]]
the products' current labeling contains the same representations for
use as those contained in the labeling used before 1938.
To qualify for exemption from the ``new drug'' definition under the
1938 ``grandfather'' clause, the drug product must have been subject to
the Food and Drugs Act of 1906, before June 25, 1938, and at such time
its labeling must have contained the same representations concerning
the conditions of its use (section 201(p)(1) of the act). Under the
1962 ``grandfather'' clause, a drug product that, preceding October 9,
1962, (1) Was commercially used or sold in the United States, (2) was
not a ``new drug'' as defined in the 1938 act, and (3) was not covered
by an approved NDA under the 1938 act, would not be subject to the
added requirement of effectiveness ``when intended solely for use,
under conditions prescribed, recommended, or suggested in the labeling
with respect to such drug.'' (Pub. L. 87-781, sec. 107(c)(4), 76 Stat.
788, note following 21 U.S.C. 321.)
FDA does not believe that any of the currently marketed products
qualify for the exemption, because the currently marketed silver
products do not appear to be the same as the silver products marketed
in the early 1900's. Unlike the silver preparations that were once
compendial articles, these new colloidal silver preparations, based on
their labeling and/or product analysis, appear to contain less silver
than the products marketed historically. Many of the products FDA has
sampled lack an ingredient declaration. Samples of some products
analyzed by FDA laboratories contained as little as 0.01 percent
silver. Analyses showed potency varied from 15.2 percent to 124 percent
of the amount of silver declared on the labels. However, FDA has not
analyzed the majority of the products on the market and, thus, is
unable to state their actual silver content.
Any person seeking to show that a drug comes within a grandfather
exemption must prove every essential fact necessary for invocation of
the exemption. (See United States v. An Article of Drug * * * ``Bentex
Ulcerine,'' 469 F.2d 875, 878 (5th Cir. 1972), cert. denied, 412 U.S.
938 (1973).) Furthermore, the grandfather clause will be strictly
construed against one who invokes it. (See id.; United States v. Allan
Drug Corp., 357 F.2d 713, 718 (10th Cir.), cert. denied, 385 U.S. 899
(1966).) A change in the composition or labeling of the product
precludes the applicability of the grandfather exemption. (See USV
Pharmaceutical Corp. v. Weinberger, 412 U.S. 655, 663 (1973).)
IV. Evidence of Safety and Effectiveness
FDA is not aware of any body of data that supports the use of
colloidal silver for the various conditions listed in the labeling
(Refs. 4 and 5) used with currently marketed products.
The 1939 book, ``Argyria, The Pharmacology of Silver'' (Ref. 7),
discussed the history and pharmacophysiologic effects of silver
administration. It included a summary chapter on the negative effects
of argyria, a permanent ashen-grey discoloration of the skin,
conjuctiva, and internal organs, resulting from the silver salts. The
book also included an index that listed proprietary silver compounds
marketed at that time.
Goodman and Gilman described colloidal silver use in earlier
editions of The Pharmacological Basis of Therapeutics (Refs. 8 and 9).
But in the 1980 edition (Ref. 10), Goodman and Gilman stated:
Claims that mild silver protein penetrates tissue at the site of
application because chloride ion does not precipitate the silver are
misleading. The large-carrier protein molecule penetrates poorly.
Fortunately, the colloidal silver preparations are now in a deserved
oblivion.
Goodman and Gilman (Ref. 10) also stated that the indiscriminate
use of colloidal silver solutions, especially in the prophylaxis and
treatment of respiratory tract infections, probably does more harm than
good. They mentioned that there is no acceptable evidence that the
routine use of silver solutions for the prophylaxis of colds is at all
efficacious, and cases of argyria have resulted from this practice.
Remington's Pharmaceutical Sciences (Ref. 11) and The Dispensatory
of the United States of America (Ref. 12) state that long-term use of
silver preparations could lead to argyria. Concerns about the side
effects of argyria may have contributed to reduced medical usage of
colloidal silver products.
The Dispensatory of the United States of America (Ref. 12) also
stated that there is no justification for the internal use of colloidal
silver either theoretically or practically.
Recently, Fung and Bowen (Ref. 13) reviewed the basic chemistry,
pharmacokinetics, pharmacology, clinical toxicology, and case reports
of adverse events of OTC silver-containing medicinal products,
including colloidal silver proteins. They concluded that silver has no
known physiologic function and that the risk of using these products
exceeds any unsubstantiated benefit.
Fung and Bowen reported that, after ingestion, up to 10 percent of
silver salts may be absorbed. Silver is deposited in many organs. The
highest concentrations are found in the skin, liver, spleen, and
adrenal glands, with lesser deposits in the muscle and brain. Argyria
is the most commonly reported adverse event and results from
accumulation of silver deposits in the skin below the epidermis.
Argyria is effectively irreversible.
As noted in section I. of this document, a number of silver salts
were evaluated as part of FDA's OTC drug review, and none was found to
be generally recognized as safe and effective for its intended use(s).
Accordingly, FDA concludes at this time that no colloidal silver
ingredients or silver salts are generally recognized as safe and
effective for OTC use.
V. The Agency's Proposal
FDA is proposing to declare all OTC drug products containing
colloidal silver ingredients or silver salts as not generally
recognized as safe and effective, misbranded, and new drugs within the
meaning of section 201(p) of the act. FDA proposes to amend subpart E
of part 310 (21 CFR part 310) by adding new Sec. 310.548 for OTC drug
products containing colloidal silver ingredients or silver salts. The
agency invites any interested parties to collect and submit any
existing data and information that support the safety and effectiveness
of colloidal silver ingredients or silver salts for any of the uses not
already evaluated under the OTC drug review. Safety data should be in
accord with Sec. 330.10(a)(4)(i) (21 CFR 330.10(a)(4)(i)) and
effectiveness data in accord with Sec. 330.10(a)(4)(ii). The agency
will evaluate these data and determine if any colloidal silver
ingredients or silver salts should not be included in new Sec. 310.548.
VI. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. National Formulary, 10th ed., pp. 517 and 520, Rockville, MD,
1955.
2. National Formulary, 12th ed., pp. 354-355, Rockville, MD,
1965.
3. The Pharmacopeia of the United States, 16th ed., pp. 643-644,
Rockville, MD, 1960.
4. Labeling brochure for ``Colloidal Silver.''
5. Reprints of articles and labeling that accompanied samples of
colloidal silver shipped through the mail.
6. Food and Drug Administration, Health Fraud Bulletin #19,
``Colloidal Silver,'' October 7, 1994.
7. Hill, W. B., and D. M. Pillsbury, Argyria, The Pharmacology
of Silver, The Williams & Wilkins Co., Baltimore, 1939.
[[Page 53687]]
8. The Pharmacological Basis of Therapeutics, Goodman and
Gilman, 4th ed., p. 1050, 1970.
9. The Pharmacological Basis of Therapeutics, Goodman and
Gilman, 5th ed., pp. 930, 931, 999, and 1000, 1975.
10. The Pharmacological Basis of Therapeutics, Goodman and
Gilman, 6th ed., pp. 976-977, 1980.
11. Remington's Pharmaceutical Sciences, 16th ed., pp. 351, 727,
and 1111, 1980.
12. The Dispensatory of the United States of America, 25th ed.,
pp. 1234-1236, 1960.
13. Fung, M. C., and D. L. Bowen, ``Silver Products for Medical
Indications: Risk-benefit Assessment,'' Clinical Toxicology, March
1996.
VII. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
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). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the proposed
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
Under the Regulatory Flexibility Act, if a rule has a significant
impact on a substantial number of small entities, an agency must
analyze regulatory options that would minimize any significant impact
of a rule on small entities. Early finalization of the regulatory
status of colloidal silver ingredients and silver salts will benefit
consumers by the early removal from the marketplace of products for
which safety and effectiveness have not been established. This will
result in a direct economic savings and public health protection to
consumers. In addition, other approved products may be available to
treat the conditions. This particular rulemaking for OTC colloidal
silver and silver salts drug products is not expected to pose a
significant impact on small business because only a limited number of
products, the agency estimates fewer than 30, would be covered by this
rulemaking. A number of silver ingredients have already been covered in
earlier rulemakings in the OTC drug review, and none were found safe
and effective for OTC human use. Under the Regulatory Flexibility Act
(5 U.S.C. 605(b)), the Commissioner of Food and Drugs certifies that
this proposed rule will not have a significant economic impact on a
substantial number of small entities. No further analysis is required.
The agency invites public comment regarding any substantial or
significant economic impact that this rulemaking would have on OTC drug
products containing colloidal silver ingredients or silver salts.
Comments regarding the impact of this rulemaking on OTC drug products
containing colloidal silver ingredients or silver salts should be
accompanied by appropriate documentation. The agency is providing a
period of 90 days from the date of publication of this proposed rule
for comments on this subject to be developed and submitted. The agency
will evaluate any comments and supporting data that are received and
will reassess the economic impact of this rulemaking in the preamble to
the final rule.
VIII. Environmental Impact
The agency has determined under 21 CFR 25.24(c)(6) 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.
IX. Request for Comments and Data
Interested persons may, on or before January 13, 1997 submit to the
Dockets Management Branch (address above) written comments and data in
response to the proposed rule. Written comments on the agency's
economic impact determination may be submitted on or before January 13,
1997. Three copies of all comments or objections are to be submitted,
except that individuals may submit one copy. Comments and data should
be identified with the docket number found in brackets in the heading
of this document and may be accompanied by a supporting memorandum or
brief. Received comments and data may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
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 under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 310 be amended as follows:
PART 310--NEW DRUGS
1. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301,
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.
216, 241, 242(a), 262, 263b-263n).
2. New Sec. 310.548 is added to subpart E to read as follows:
Sec. 310.548 Drug products containing colloidal silver ingredients or
silver salts offered over-the-counter (OTC) for the treatment and/or
prevention of disease.
(a) Colloidal silver ingredients and silver salts have been
marketed in over-the-counter (OTC) drug products for the treatment and
prevention of numerous disease conditions. There are serious and
complicating aspects to many of the diseases these silver ingredients
purport to treat or prevent. Further, there is a lack of adequate data
to establish general recognition of the safety and effectiveness of
colloidal silver ingredients or silver salts for OTC use in the
treatment or prevention of any disease. These ingredients and salts
include, but are not limited to, silver proteins, mild silver protein,
strong silver protein, silver chloride, and silver iodide.
(b) Any OTC drug product containing colloidal silver ingredients or
silver salts that is labeled, represented, or promoted for the
treatment and/or prevention of any disease is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act) for which an approved application or abbreviated
application under section 505 of the act and part 314 of this chapter
is required for marketing. In the absence of an approved new drug
application or abbreviated new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product containing colloidal silver or silver salts labeled,
represented, or promoted for any OTC drug use is safe and effective for
the purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After (date 30 days after date of publication of the final rule
in the Federal Register), any such OTC drug product containing
colloidal silver or silver salts initially introduced or
[[Page 53688]]
initially delivered for introduction into interstate commerce that is
not in compliance with this section is subject to regulatory action.
Dated: October 9, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-26371 Filed 10-11-96; 8:45 am]
BILLING CODE 4160-01-F