This from CS Pro.

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[Federal Register: August 17, 1999 (Volume 64, Number 158)]
[Rules and Regulations]
[Page 44653-44658]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17au99-6]

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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 [same thing?]

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
establishing that all over-the-counter (OTC) drug products containing
colloidal silver ingredients or silver

[[Page 44654]]

salts for internal or external use are not generally recognized as safe
and effective and are misbranded. FDA is issuing this final rule
because many OTC drug 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: This regulation is effective September 16, 1999.

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

In the Federal Register of October 15, 1996 (61 FR 53685), FDA
published a proposed rule to declare that all OTC drug products
containing colloidal silver ingredients or silver salts are not
generally recognized as safe and effective, and are new drugs and
misbranded within the meaning of section 201(p) of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 321(p)). Colloidal silver
is a suspension of silver particles in a colloidal base. [what are silver salts?] In recent
years, colloidal silver preparations of unknown formulation have been
appearing in retail outlets. These products are labeled for numerous
disease conditions, many of which are serious diseases. The dosage form
of these colloidal silver products is usually oral, but product
labeling also contains directions for topical and, occasionally,
intravenous use.
FDA has not approved a new drug application (NDA) for any colloidal
silver product. None of the silver salts evaluated as part of FDA's OTC
drug review was found to be generally recognized as safe and effective
for its intended use(s). FDA is not aware of any substantial scientific
evidence that supports the use of OTC colloidal silver ingredients or
silver salts for disease conditions. The agency invited 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. Interested persons were invited to submit written comments
on the proposed regulation and on the agency's economic impact
determination by January 13, 1997.
In response to the proposal, the agency received 251 responses.
Copies of these comments are on public display in the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. Additional information that has
come to the agency's attention since publication of the proposal is
also on public display in the Dockets Management Branch.
Based on the information set forth in the proposed rule, and after
consideration of the information submitted by the public comments (as
summarized as follows), FDA is declaring that all OTC drug products
containing colloidal silver ingredients or silver salts are not
generally recognized as safe and effective, and are new drugs and
misbranded within the meaning of section 201(p) of the act. Adequate
safety and effectiveness data have not been provided to establish
general recognition of the safety and effectiveness of colloidal silver
or silver salt ingredients for any OTC drug uses.[nor has adeqaute evidence been provided to establish ineffictiveness or lack of safety] The data submitted
did not include the required absorption, metabolism, tissue
distribution, accumulation, excretion, and pharmacodynamics (effect of
the drug at its action site) of silver in the body, both when taken
internally and applied externally, and of the effect of the particle
size of the silver on these systemic effects.
FDA is amending subpart E of part 310 (21 CFR part 310) to add
Sec. 310.548 for OTC drug products containing colloidal silver
ingredients or silver salts. The agency has expanded proposed
Sec. 310.548(a) to include some additional silver ingredients.

II. Public Comments and the Agency's Response

A. General Comments

1. Many comments agreed with the proposed rule. One of these
comments cautioned against the dangers of using untested drugs and
recalled that Laetrile misled unsuspecting people in search of a quick
cancer cure. Another comment provided personal experience as a victim
of argyria who had been disfigured for 40 years as a result of using
colloidal silver. This comment included an excerpt from a book that
recorded 114 cases of argyria compiled in the 1930's. The comment
contended that many marketers of colloidal silver deny the potential
for harm and often misquote or distort the historical articles dealing
with these products. [No one else would do that, now would they?]
A physician, who was formerly a pharmacist, recounted his own
experience in reviewing cases of argyria. The victims had ingested
silver products in the 1940's and 1950's. [What silver products, at what dosage, for how long?] The physician was concerned
that a product that does not have any rational use would lead to the
redevelopment of argryia as a clinical problem. Another physician/
ophthalmologist commented that colloidal silver is dangerous quackery.
The agency appreciates these comments in support of its proposal. [But no other comments to the contrary]

B. Comments on Safety and Effectiveness

2. One comment expressed concern that many different silver
products being marketed are inferior products and are not even true
colloids. Another comment stated that the vast majority of silver
products being sold are fraudulent products. The comment noted that it
had tested a number of these products and found that several actually
had no silver content, one did not contain the silver particle size as
stated on the label, and only one product exceeded all stated purity
and stability claims found on the label. The comment added that many of
the products were only duplicates of older colloidal silver products.
The comment considered these ``newer'' products as having the same
dangers, intermittent effectiveness, and lack of stability as the older
products. The comment contended that the vast majority of the colloidal
silver products it tested are totally useless, some were dangerous to
ingest, and some were possibly a threat to life. [..and the useful products?]

The comment stated
that it is a major problem to keep off the market these so-called
``colloidal silver'' products that contain significant amounts of
silver ions [Isn't that what colloidal silver is?] and silver salts. The comment suggested a revision of the
United States Pharmacopeia (USP) specifications for these products.
Another comment stated that many of the colloidal silver products
it analyzed are considered ``Bredig Sols'' (simple colloidal silver),
referring to Bredig, Heidelberg, 1893. The comment added that a pure
Bredig Sol is simply elemental silver in distilled water, while some
Bredig Sols are mixed with saline to make them isotonic. The comment
mentioned that the silver content in these products (a viable product
could contain 0.005 percent silver) is many magnitudes less than the
silver content of the products discussed by FDA in its safety and
effectiveness evaluation (61 FR 53685 at 53686). The comment contended
that the agency had not reviewed the Bredig Sols and disagreed with the
agency's assumptions that there is an analogous comparison between
colloidal silver proteins and other silver compounds to a simple Bredig
Sol.

[[Page 44655]]

These comments highlight the existing problems in trying to
establish whether any silver salts or colloidal silver ingredients can
be generally recognized as safe and effective. Because of the
acknowledged differences in silver content and particle size of the
silver in various products, it is difficult to draw conclusions from
clinical studies conducted on different silver products. The agency has
minimal manufacturing controls information on these products. The
agency does not have information that assures the strength, quality,
purity, and potency of various silver products used in clinical studies
and other reports included in the comments.
Concerning the comment suggesting a revision of USP specifications,
the proposed rule stated that none of the formerly recognized colloidal
silver preparations (e.g., colloidal silver iodide, strong (or mild)
silver protein, ammoniacal silver nitrate solution) has been official
in the USP or the National Formulary (N.F.) since 1975. It is
industry's responsibility to have these silver ingredients reinstated
in the USP or N.F. and to revise the specifications used in the former
compendial monographs. Concerning ``Bredig Sols,'' the comment did not
provide any specific safety and effectiveness data; thus, the agency is
not able to establish that such products are generally recognized as
safe and effective. [or not]
3. Several comments submitted information purporting to support the
safety of colloidal silver and other silver ingredients. The comments
contended that silver is nontoxic and has minimal side effects. One
comment stated that silver is poorly absorbed and not readily retained
in the body when taken orally. Another comment stated that colloidal
silver is harmless to the liver, kidneys, other internal organs, human
enzymes, and the eyes; contains no free radicals; and has no reaction
with other medications. Several comments mentioned that argyria, a blue
skin discoloration resulting from prolonged administration of silver
compounds and accumulation in the body, is the main side effect that
occurs. One comment explained that argyria occurs because a small
amount of the silver compound is absorbed and deposited in the skin,
where it is reduced by light to metallic silver; the resulting skin
discoloration persisting almost indefinitely, although there are no
associated toxic effects. The comment contended that colloidal silver
is the only known form of silver that is not deposited under the skin
even with large doses. Another comment added that most of the reported
cases of argyria resulted from the use of silver nitrate, various ionic
silver salts, or highly concentrated mild silver protein. The comment
concluded that the dilute, mild silver protein products marketed today
are similar to pre-1938 colloidal silver solutions and do not cause
argyria. The comment also discussed the levels of silver in the
majority of silver products marketed today and indicated that the
amount of silver ingested from these products and the diet are within
the Environmental Protection Agency's maximum daily exposure reference
dose of 350 micrograms per day for a 70 kilogram (kg) adult.
Another comment presented the results of several animal (rat)
studies involving acute or chronic administration of various amounts of
colloidal silver (mild silver protein in colloidal suspension),
approximately 1,500 parts per million (ppm),[WOW!] either by intravenous (IV)
injection or in drinking water. The IV studies included an initial
acute dose finding study followed by a chronic study (0.15 or 0.015
milligram (mg) per 1 milliliter (mL)). Two groups of four rats received
each dosage; two rats served as controls and received 1 mL of
physiological saline solution. Each rat received a total of 12
injections. The investigator reported that no abnormal clinical or
behavioral signs were observed after 12 days of treatment. In another
followup chronic IV rat study, three rats were injected with 1,500 ppm
colloidal silver three times per week for 4 weeks (a total of 18 mg per
300 gram (g) rat), and three rats served as controls. All treated and
control rats were weighed at the time of injection. At the completion
of the study, there were no differences in body weight and no clinical
signs or gross pathologic changes between the treated and control
groups. The drinking water study involved 15 rats fed 1.5 ppm mild
silver protein solution in their drinking water for 40 days. The rats
showed no clinical signs of gross pathological changes at the end of
the treatment period. Three rats received regular drinking water and
served as controls. The investigator stated that the data do not
provide information about the metabolic fate of the silver, but support
safety if extrapolated to humans because a 60-kg person would have to
be given 3,600 mg to receive an amount equivalent to the rats' highest
dose (18 mg/300 g rat).
The agency does not consider this information adequate to establish
general recognition of the safety of silver salts or colloidal silver
ingredients for OTC drug use. The comments themselves indicate that
ionic silver salts and highly concentrated mild silver protein clearly
are not safe for OTC use. The animal data indicate that mild silver
protein in colloidal suspension at low concentrations may be safe in
rats when administered in specific concentrations for up to 40 days.
Additional data are needed in humans on the absorption, metabolism,
tissue distribution, accumulation, excretion, and pharmacodynamics of
silver in the body, both when taken internally and applied externally,
and of the effect of the particle size of the silver on these systemic
effects. [no question there] The agency concludes that a full pharmacologic profile that is
relevant to human use is needed.
4. Several comments submitted information purporting to support the
effectiveness of colloidal silver and other silver ingredients. One
comment provided a partial list of the more than 650 diseases that
colloidal silver has been used against and included a number of
testimonials. Another comment stated that silver will kill 650 disease
organisms, but it does not cure 650 diseases. [possibly true] The comment added that a
Bredig Sol of silver at 30 ppm is an effective germicide for both gram-
positive and gram-negative bacteria, fungi, yeasts, and viruses.
Another comment noted the antimicrobial and bacteriostatic effects of
diluted colloidal silver protein solutions. One comment provided a
number of case reports involving the use of a colloidal silver (200
ppm) suspension with protein and distilled water and a mild silver
protein cream to treat various conditions (e.g., rash, pain, and sore
gums).
Another comment, from a physician, described a double-blind
clinical study that he conducted using a commercial colloidal silver
product (concentration not provided) in 22 men ages 50 to 82, with a
mean age of 61.9 years. The physician obtained a brief medical history
from each man and did a rectal examination. The men reported that
nocturia (frequency of urination) ranged from one to five times a
night. The physician assumed that the men had benign prostatic
hypertrophy because of their age and the onset of symptoms in recent
years. Of the 22 men, 15 took colloidal silver and 7 took placebo
(colored water). The dose was 1 teaspoon (tsp) of the products morning
and evening, and the duration of the study was from 19 to 23 days, with
one exception of 10 days for a late entry. At the end of the study,
four men (all on the colloidal silver) reported considerable
improvement in the nocturia, with a reduction from 2 to 4 times to 1
time each night, while six other men (five on the colloidal silver)
noted some improvement in the nocturia. Two men with a history of

[[Page 44656]]

transurethral resection of the prostate, who were on the colloidal
silver, did not report any improvement.
Subsequently, all of the men continued on colloidal silver (1 tsp
daily) for the next 8 weeks. The men were interviewed after about 4
more weeks, and each completed an American Urological Association (AUA)
Symptom Index representing symptoms at the time of the interview. The
men also completed an AUA index representing symptoms before starting
the colloidal silver. The AUA index is based on answers to seven
questions, graded from 0 (not at all) to 5 (almost always), with the
score being a sum of the answers to the questions. The one man who
reported improvement on placebo reported marked improvement on the
colloidal silver, with his nocturia decreasing from 2 to 3 times to 1,
and occasionally 0, time each night. His AUA index was 9+ at the
beginning and improved to a 3 at the last interview. One man moved, and
a followup was not obtained. Of the remaining 21 men, 16 reported
improvement of varying degrees. All reported decreased nocturia, with
five men recording an improvement of 2 or less on the AUA index and
nine men reporting an improvement of 3 to 10 on the AUA index. One man
reported that he had been taking a prescription drug for benign
prostatic hypertrophy before starting the colloidal silver. The last
two men had improvements of 14 and 18 on the AUA index, with nocturia
decreasing by 3 and 2 times, respectively. Five men reported no
improvement during the study. Two of these men had a history of
transurethral resection of the prostate, one had been taking a
prescription drug for this condition for the past 6 months and his
nocturia had already improved to 1 time each night, and the other two
had been having symptoms for 6 and 15 years, respectively, and had an
enlarged prostate when the study began. The physician noted that
because the four men with a tender prostate improved, it was reasonable
to suggest that the beneficial action of the colloidal silver was due
to its antibacterial activity. He hypothesized that there may be some
subclinical prostatitis in many men with benign prostatic hypertrophy,
and this might explain why the colloidal silver resulted in a
remarkable reduction in the men's symptoms. The physician concluded
that the results of this study merit further investigation by the
medical community.
The physician also commented on some other observations from about
50 men who had taken colloidal silver (most for symptoms of prostatism)
under his direction before, during, and after the study (a period of
about 6 months). Six noted clearing of acne or other infectious lesions
of the skin, three reported improvement of mucus in the throat and
associated cough of long duration, two indicated that irritation around
the anus had cleared, one stated that he had no summer colds for 3
months (which was unusual for him), eight reported improvement in nasal
discharge and sinus trouble (especially when using colloidal silver in
a nasal spray), two noted a reduction in upset stomach and abdominal
pain, and two reported that their sexual enjoyment and performance had
improved. The physician concluded that these observations suggested
some areas that needed to be investigated further.
The agency finds that the previous studies are not adequate and
well-controlled clinical studies of the type described in Sec. 314.126
(21 CFR 314.126) that need to be conducted. The studies have major
methodic flaws. There needs to be a clear statement of the objectives
of the investigation and a protocol containing a specific study design,
the method of subject selection (with inclusion and exclusion
criteria), the method of assigning subjects to treatment and control
groups, well-defined methods for measuring the subjects' responses, and
methods for analysis of the study results. Adequate measures need to be
taken to minimize bias on the part of the subjects, observers, and
analysts of the data, which is done by adequate blinding. The agency is
unable to determine the adequacy of the blinding in the physician's
study because the placebo was described as ``colored water.'' The
agency is not able to ascertain the degree of similarity or difference
that existed in the appearance of the colloidal silver product and the
placebo to determine how well the study was blinded. The studies need
replication by other investigators and need to follow Sec. 314.126.

[ very well and good, so, who does the studies the "agency" will accept?]
Likewise, the conditions described in the case reports provided by one
comment need to be studied in adequate and well-controlled clinical
trials. Finally, the information that silver will kill 650 disease
organisms and that a Bredig Sol of silver at 30 ppm is an effective
germicide for both gram-positive and gram-negative bacteria, fungi,
yeasts, and viruses needs to be related to in vivo treatment for
specific disease conditions. The agency concludes that the data and
information submitted are not sufficient to establish general
recognition of effectiveness [or ineffectiveness] for colloidal silver or other silver
ingredients for any specific OTC condition.

C. The Grandfather Clauses of the Act

5. One comment claimed that the silver products marketed today are
the same as the more dilute mild silver protein products marketed pre-
1938 that did not cause argyria. The comment made the following
recommendation: FDA should set guidelines of the acceptable levels of
the solutions and the dosage based on current EPA safety standards and
what was available pre-1938, so that a ``grandfathered'' standard is
implemented. Another comment stated that not approving its colloidal
silver product as a grandfathered colloidal silver would be to deprive
the public of the use of an extremely safe and effective product
already in use for 4 years.
The ``grandfather exemption'' was discussed in detail in the
proposed rule (61 FR 53685 to 53686). None of the comments provided any
evidence to show that the composition and the labeling of colloidal
silver or silver salt drug products have remained unchanged since 1938
or 1962. [Unchanged? As consistantly inaccurate as every other pre 1930s drug would be "unchanged"!]Without such evidence, the products cannot qualify for either
grandfather exemption, and there is no need to set any guidelines as
requested by one comment.

D. Freedom of Choice

6. A number of comments included individual testimonials or
expressions of belief that colloidal silver benefited their health and
that of their family members or friends. A few comments mentioned
benefits experienced by pets. Many of the comments stated that the
proposed rule would deny them the freedom of choice to select their own
drugs.
FDA's statutory mandate includes protection and promotion of the
public health by ensuring that drugs are not only safe but also
effective for their intended use. The Commissioner of Food and Drugs'
decision on the status of Laetrile, published in the Federal Register
of August 5, 1977 (42 FR 39788), expresses the agency's position on
freedom of choice with respect to ensuring that drugs are not only
safe, but also effective. That statement reads in part:
In passing the 1962 Amendments to the act--the amendments that
require that a drug be proved effective before it may be marketed--
Congress indicated its conclusions that the absolute freedom to
choose an ineffective drug was properly surrendered in exchange for
the freedom from the danger to each person's health and well-being
from the sale and use of worthless drugs * * *. To the extent that
any freedom

[[Page 44657]]

has been surrendered by the passage of the legislation which bans
from the marketplace drugs that have not been proven to be
effective, that surrender was a rational decision which has resulted
in the achievement of a greater freedom from the dangers to health
and welfare represented by such drugs.
Agency regulations in 21 CFR 330.10(a)(4)(ii) state that the
standards for effectiveness for an OTC drug that is generally
recognized as effective include a requirement for controlled clinical
investigations. Isolated case reports, random experience, and reports
lacking the details that permit scientific evaluation are not
considered adequate to establish effectiveness. [Nor have standardized tests been preformed to establish the opposite] Testimonials from
consumers cannot be considered as adequate proof of effectiveness or
safety. None of the comments presented any evidence of safety or
effectiveness beyond personal experience.[on either side of the issue]
In the absence of data demonstrating that the ingredients present
in OTC drug products containing colloidal silver ingredients or silver
salts are generally recognized as safe and effective, these ingredients
cannot be included in an OTC drug product. After the effective date of
the final regulation, any such OTC drug product initially introduced or
initially delivered for introduction into interstate commerce (unless
it is the subject of an approved NDA, of which there currently are
none) that is not in compliance with this regulation will be subject to
regulatory action.

E. The Dietary Supplement Health and Education Act (DSHEA)

7. Several comments, from consumers, stated that the specific
product they used did not make any claims and might be considered a
dietary supplement. [It may also be considered to be just what it says on the label..colloidal silver..use it as you may.] None of the comments provided any labeling or
specifics about the products they used.
This final rule addresses products marketed as OTC drugs. A product
that is not intended for OTC ``drug'' use in accord with section
201(g)(1) of the act would not be subject to this final rule. A product
containing silver could, under certain circumstances, be marketed as a
dietary supplement if it meets the definition in section 201(ff) of the
act and other applicable requirements. Among other things, such a
product's label must state that the product is a dietary supplement and
meet other labeling requirements of the act. (See, e.g., section
403(q), (r), and (s) of the act (21 U.S.C. 343(q), (r), and (s)).) It
must also meet the safety requirements of the act. (See, e.g., 21
U.S.C. 342(a), (f), and (g).) FDA may take regulatory action against a
product marketed as a dietary supplement when authorized to do so by
the act.
A dietary supplement containing colloidal silver or silver salts
may not be labeled in whole or in part for topical use. Section
201(ff)(2)(A)(i) of the act requires that a dietary supplement is a
product that is ``intended for ingestion.'' The term ingestion has been
addressed by the court in United States v. Ten Cartons, Ener-B Nasal
Gel, 888 F. Supp. 393 (E.D.N.Y.), aff'd, 72 F.3d 285 (2d Cir. 1995). A
topical product could not be a dietary supplement.

III. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
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, 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 the rule on small
entities.
Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et
seq.) requires that agencies prepare a written statement and economic
analysis before proposing any rule that may result in an expenditure in
any one year by State, local, and tribal governments, in the aggregate,
or by the private sector, of $100 million (adjusted annually for
inflation). As the agency stated in the proposed rule, this rulemaking
is not expected to pose a significant impact on small business because
only a limited number of products are affected (61 FR 53685 at 53687).

[ ALL of small businesses products are limited in number]
The agency believes that this final rule is consistent with the
principles set out in the Executive Order and in these two statutes.
The purpose of this final rule is to establish that all 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. The agency's Drug Listing System
identifies a multitude of silver-containing products. These products
may contain silver, silver ion, silver chloride, silver cyanide, silver
iodide, silver oxide, or silver phosphate.
All of these manufacturers are considered small entities,[who most certainly don't have $100 million hanging around] using the
U.S. Small Business Administration designation for this industry (750
employees).
Manufacturers will no longer be able to market OTC drug products
containing any silver ingredients after the effective date of the final
rule. While the manufacturers may incur a loss of revenue from some of
these products, some silver products for internal use may be able to
continue to be marketed as dietary supplements, provided they meet,
among other regulatory requirements applicable to dietary supplements,
the definition of dietary supplements in section 201(ff) of the act and
meet the labeling requirements of section 403 of the act.
Manufacturers have been aware of the possible effects on the status
of these OTC silver drug products since October 1996 and have not
submitted adequate safety and effectiveness data to the agency. Since
publication of the 1996 proposal and with the 30-day implementation
date after publication of the final rule, manufacturers should have
ample time to deplete most of their remaining stock of OTC drug
products containing the affected ingredients.
The agency has considered a longer effective date for this final
rule. However, manufacturers have not submitted the necessary data, and
safety and effectiveness have not been established for the ingredients
included in this final rule. Consumers will benefit from the removal
from the marketplace of OTC drug products containing ingredients for
which safety and effectiveness have not been established. If consumers
purchase these products marketed as dietary supplements and if the
product bears a statement claiming a benefit related to a classical
nutrient deficiency disease and discloses the prevalence of such
disease in the United States, describes the role of a nutrient or
dietary ingredient intended to affect the structure or function of the
body in humans, characterizes the documented mechanism by which a
nutrient or dietary supplement acts to maintain such structure or
function, or describes general well-being from consumption of a
nutrient or dietary ingredient, then the labeling will have to inform
them that ``This statement has not been evaluated by the Food and Drug
Administration. This product is not intended to diagnose, treat, cure,
or prevent any disease.'' (See 21 U.S.C. 343(r)(6).)
While this final rule may cause manufacturers to discontinue
marketing or reformulate or relabel some products, these manufacturers
have known for some time that if adequate data were not submitted to
support safety and effectiveness, cessation of marketing of the current
OTC drug products would be required, in any event, when the final

[[Page 44658]]

rule was published and became effective.
The analysis shows that this final rule is not economically
significant under Executive Order 12866 and that the agency has
considered the burden to small entities.[sure did!] Thus, this economic analysis,
together with other relevant sections of this document, serves as the
agency's final regulatory flexibility analysis, as required under the
Regulatory Flexibility Act. Finally, this analysis shows that the
Unfunded Mandates Reform Act does not apply to the final rule because
it would not result in an expenditure in any one year by State, local,
and tribal governments, in the aggregate, or by the private sector, of
$100 million. [so 'nuff..]

IV. Paperwork Reduction Act of 1995

This final rule contains no collections of information. [Interesting comment!] Therefore,
clearance by the Office of Management and Budget under the catch22 Paperwork
Reduction Act of 1995 is not required.

V. 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.

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, 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.

2. Section 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, silver ion, silver chloride, silver
cyanide, silver iodide, silver oxide, and silver phosphate.
(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 as set forth in part 312
of this chapter.
(d) After September 16, 1999, any such OTC drug product containing
colloidal silver or silver salts initially introduced or initially
delivered for introduction into interstate commerce that is not in
compliance with this section is subject to regulatory action.

Dated: July 14, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-21253 Filed 8-16-99; 8:45 am]
BILLING CODE 4160-01-F

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What I believe to be the Real 'STORY' behind the FDA Ruling against CS.
Bruce Marx, N.D., CS PRO Systems

On August 17, 1999, the FDA 'finalized' its ruling against all OTC (over the counter) Drugs containing colloidal silver
ingredients or silver salts, to become effective within 30 days, as of September 16,1999.

On October 15, 1996 the FDA published the 'proposed' rule and gave the CS 'industry' until August 17, 1999 to
provide the 'studies' demonstrating the 'claims' being made by the 'industry' relative to applications, uses,
effectiveness, safety, etc. of colloidal silver, in its numerous forms and formulations. During this time frame the only
thing that was produced and provided to the FDA were 251 responses, of which a small percentage were negative,
and the balance being basically 'testimonials', with a very few 'studies' which were conducted on a small scale in
uncontrolled conditions, some even by 'medical professionals'. However, nothing was presented in the 'format', and
following the 'guidelines', required by the FDA to constitute a 'study' acceptable for consideration for approval.
Therefore, with no 'proof' to the contrary, the FDA finalized the 'Rule'.

So how did all this come about? This is what I think, based on being in the business for nearly 10 years and
'observing' the increasingly sorry 'state of affairs' in the industry over this period.

Silver has been recognized for its antiseptic properties for centuries. Somewhere, way back, it was theorized that if
the silver could be converted into something which could be administered internally it would be much more effective
in fighting disease, so it was crudely ground into a powder form. The next stage was to get it into a 'liquid', whereby
its usefulness could be much better utilized. This liquefaction was accomplished by dissolving the silver with powerful
acids, such as nitric acid, which produced silver nitrate. Silver nitrate was used extensively by the medical community
up through the mid 1900's, and is still in limited use in some areas even today. In the early 1900's it was discovered
that silver could be reduced to small (comparatively speaking) particles by applying a DC electrical current through
two silver electrodes suspended in water. This was the beginning of what we know today as "colloidal silver".
Somewhere along the way, someone found that you could produce colloidal silver by putting a few batteries in series,
and build a small, portable, colloidal silver 'generator'. Around the mid to late eighties this idea really caught on and
the aggressive 'promotion' of colloidal silver began. Soon enterprising individuals began adding 'bells and whistles' to
the little black boxes and bottling the DC colloidal silver, selling it extensively on the market. Of course there were
no quality standards or controls, and very few producers had any idea what concentration they were making.

This began to attract the attention of the FDA. However, colloidal silver had been around for quite awhile before the
FDA came into existence in 1938. So in 1991, someone got the FDA to write a letter basically stating that as long as
'it' (CS) was produced and marketed the same way it had been prior to 1938, it would be considered a 'grand fathered
modality'.

At the same time, the internet was 'taking off'. Between the ability to market the product for next to no cost, the high
price colloidal silver was bringing off the shelf in stores, and numerous 'MLM' operations, 'garage and basement
operators' began showing up all over the place. First there were hundreds, and then thousands, of small CS
producers, all over the internet, and the world. The famous 'FDA approval letter' was the rallying cry of these
marketers; "FDA approved as a pre 1938 modality", and "CS is FDA approved", began showing up on many products
and in nearly all advertisements for colloidal silver. About the same time the mysterious "List of 650 diseases which
CS was 'known' to cure prior to 1938" was first mentioned. By the way, I have never seen, or been able to find, this
supposed list, nor have any of my customers.

At this point, lets step back and take a look at the situation:
1. Discovering colloidal silver, seeing the average selling price, finding that the total cost to set up in the CS
business is only a case of 9 volt batteries and some silver wire, and the only other costs are the 'water' and 'time',
hundreds of people began going into the CS business, mostly in filthy garages, basements, or other unsanitary
situation, part-time, and after their 'day job'.
2. We now have thousands of people producing 'who knows what' and selling it as colloidal silver, with FDA approval
(?).
3. For the sake of 'marketing hype', CS products began appearing with various things 'added', such as 'protein',
hyped as "MSP".
4. Some began adding other 'stabilizing' agents, so they can keep their particles in suspension longer, while
neglecting to mention this on the label.
5. To achieve the touted 'golden yellow color', many were adding food coloring to their product, with no mention on
the label.
6. Some of the less scrupulous were marketing CS products which had no silver at all, only food coloring.
7. AND, all of these products are being 'represented' as FDA approved!
8. Then came the 'list of 650', (unsubstantiated claims) for the effectiveness of CS in general, and hyped all over the
place.
9. With all the commotion about CS, the 'big boys' (pharmaceuticals and medicos), knowing the 'potential' of CS and
seeing that there is a popularity 'groundswell' which could potentially cut into their 'bottom line', are beginning to get
concerned.
10. The FDA is casting a watchful eye on the colloidal silver industry in general, for their 'unethical' practices.

Where do we go from here? Well, in the midst of all the 'hoopla' the 'big boys' (pharmaceuticals and medicos) smell
an opportunity. They procure an assortment of various CS products from the marketplace and have them analyzed.
They find that virtually ALL of the products are 'mislabeled', claiming concentrations of silver (PPM) which are 'not'
in the products. Many have 'stabilizers' added with no mention of this on the label. Some of the products have no
silver content whatsoever (but possess a deep yellow color), and a few actually have bacteria growing in the CS(?).
They see the 'state of the industry', the multitude of 'sub-standard' products, the 'unapproved' claims being made
(including AIDS and cancer), and a potentially hazardous situation: products with 'bacteria' growing in them.

What an opportunity to get CS out of their hair!! So 'they' (or they had individuals do it for them) go to the FDA and
file a series of complaints about CS, presenting this 'evidence'. At this point, the FDA is obligated to 'investigate'.
They do, they find the same results, and begin drafting a 'rule' which they 'proposed' in October, 1996. The FDA gave
the CS industry until August of 1999 to 'prove' (provide the studies for) their claims.

Therein lies the 'RUB'! Once within the realm of the FDA, the 'process' requires that 'studies' must be done and the
results submitted to the FDA for 'approval'. The problem is, what applies to Peter also applies to Paul - there is NO
'double standard'. In other words, the 3 year, 'triple blind', 1500 subject, meticulously controlled, through numerous
repetitions, precisely documented, and recorded study, that costs a pharmaceutical company 100's of millions of
dollars to get a new 'drug' approved, would also be required of the CS industry, and would need to be in strict
accordance with FDA 'requirements and guidelines'. The 'big boys' concluded that there was no organization, or
individual, within the CS industry having the financial wherewithal to subsidize any such 'studies'. Without 'control' of
the product, there is no possibility for a return on investment, and no one would put that kind of money into a
'guaranteed loss' situation. They were right! In fact, these 'study' procedures would need to be done for each
'individual manufacturers product', and separately for each 'individual claim' made. As an example, a colloidal silver
manufacturer with a single product, wishing to submit studies for approval for only 10 claims, would need to conduct
and submit 10 'individual studies' at a total expenditure of ONE BILLION DOLLARS! Welcome to the 'big league'
CS'ers!

Needless to say, between 1996 and 1999, the 'proposed rule' was basically ignored by most producers, except to use
it as 'marketing hype' to sell their product; "Get your CS today before the FDA takes it away - BUY NOW - BUY
NOW"! Meanwhile, the 'snake oil salesmen', 'shysters' and the 'greedy ignorant' continued to flood into the market
for the 'fast/easy' buck! The proliferation of 'junk CS' continued to increase at a phenomenal rate. The 'claims' were
not only continued, but expanded! The products couldn't get much worse - there was just more of it! And the FDA
was not sleeping while all this was going on!

So when the end came, and no one was able to produce the 'required studies' - for ANY CS products - the rule was
finalized (August 17, 1999)! Additionally, since the 'proposed rule' was not only 'ignored', but used to support the
"Buy Now" marketing ploy, the FDA had no reservations whatsoever in making the 'final rule' effective within only
30 DAYS (September 16, 1999) of finalization! Punitive punishment? I wouldn't doubt it!

Does the CS industry deserve this kind of treatment? YOU look at the situation and decide for yourself. Personally I
have been watching, knowing for years that this would be the end result! Who do we blame? The FDA? Personally, I
don't like the bureaucracy any more than the next 'patriot', but in this instance, I cast the blame on the greedy
'snake-oil salesmen' that inundated the CS industry for the sole sake of 'easy profit'! The FDA was merely 'doing
their JOB' (and initially with some 'reluctance', it appears).

The FDA decision was announced via a short "FDA TALK LETTER", which only 'brushed over' the highlights of the
entire 'rule'. In itself, the letter 'indicated' that the products in question were only those containing 'protein', and
silver oxide. Those who go only by the 'Talk Letter' are 'cruising for a bruising'! They 'think' that the 'ruling' does
not affect them, so they can continue to promote their 'junk' freely! Surprise! If one reads the entire 'Rule', basically
anything with silver in it is included!

The only 'fortunate' thing is that the people responsible for this happening are inherently 'lazy' (EASY money) and
they will not take the time or effort to do any research. To prove this point, look at the dearth of information which
has been generated relative to CS! Over 80% is the same 'garbage', reshuffled, reorganized, and regurgitated in
different formats! Another 10% is 'techno-gobbledygook' which the average consumer cannot comprehend or
understand, 'insinuating' that the author MUST be 'correct' (?).

A little note here: In working with the FDA for 'approval', the topic of 'enforcement' came up, and I was advised, in
no uncertain terms, that this rule was to be "VIGOROUSLY ENFORCED"! I am guessing at this, but I suspect
$5000 per 'violation', and 'each bottle sold' being a single violation, will be a likely 'fine'! The cost of 'ignorance', or
'arrogance' could become very expensive, very quickly!

Unless CS producers invest in their own (approved and accurate) testing capabilities (most won't - too expensive and
somebody has to operate it - 'techie wages'), or pay for 'certified analysis' on everything they make (which they won't
- they proved that in the past), they WILL be caught for 'mislabeling'! Last year we analyzed over 30 different
manufacturers products (off the shelf) and not a single one had even 50% of what they 'claimed' on their (mis) labeled
bottle! Many of these were "(?) reputable(?)" bigger name products! It is very discouraging to me (as the 'layers' are
removed, one by one), to see out how little even the 'bigger' distributors of CS know about the 'science' of what they
are selling! This is what happens when 'marketing' (and profit motive) take control over 'basic science'. To their
advantage, these 'bigger' organizations market a multitude of products, so dropping one product (when the pot gets
too hot) doesn't hurt them that badly (compared to their 'exposure'), but it does affect the availability of CS to the
consumer!

Was the FDA 'Talk Letter' a psychological 'coup'? I think so. I believe they KNOW the effectiveness and safety of
CS, which is why they have ignored it for so long (until forced into action by the 'complaints'). I also believe that they
knew that anyone 'seriously in the CS business', and producing a 'quality product', would read the 'entire rule',
consult with the FDA, and act accordingly (they even provided 'us' with an 'OUT', buried within the rule). I'll bet they
figured that the 'limited information' provided in the letter would keep the 'culprits' around long enough for them
(FDA) to 'bust' them. This is the strategy I would use to separate the 'wheat from the chaff'!

Meanwhile, thanks to the greed of the aforementioned individuals, colloidal silver can no longer be sold as an 'OTC'
drug (most CS products fit this classification). I have already had many contacts from people who have found CS
'missing' from the shelves of their local health food store, or have gone to the internet only to find a glaring notice
that colloidal silver is "no longer available". Rest assured that CS PRO will do everything we can to continue to
provide you with our 'quality' product.

I am not a 'supporter' of the FDA, or any other 'bureaucratic organization' (FBI, BATF, FEMA, etc.), but in this
instance I don't see that they had any choice. Obviously, there cannot be a 'double standard', as the 'big guys' would
exploit this to the hilt! The action was predictable, and 'mandated'. Manipulated? Perhaps you could say the
'complaints' were a manipulation. But in any case, the only ones we have to blame are ourselves (the CS industry), for
allowing the 'infiltration' of the 'snake-oil salesmen'.