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September 9, 2003

Dockets Management Branch (HFA 305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

**RE: DOCKET NO. 96N-0417, GOOD MANUFACTURING PRACTICES**

**FOR DIETARY SUPPLEMENTS**

**TOPIC: ECONOMIC IMPACT OF THE PROPOSED RULE**

This is the [sixth]{.underline} in a series of comments submitted by the
Council for Responsible Nutrition regarding the above-mentioned proposed
rule. These comments will address the economic impact of the proposed
rule.

CRN requested and was granted additional time for submission of these
comments, in order to permit us time to evaluate new information
obtained pursuant to a FOIA request for underlying data not previously
included in the administrative record, relating to FDA's assumptions and
calculations on the estimated economic impact of the rule. Using only
the information published in the *Federal Register*, we were unable to
reproduce FDA's calculations and therefore prepare our own fully
comparable estimates.

In the preparation of these comments, we have relied heavily upon the
expertise of the firm of Glassman-Oliver Economic Consultants, Inc.,
specifically the analytical talents of Neil Grossman, Senior Research
Analyst, and the analysis and policy guidance of Stephen Stockum, Ph.D.,
Senior Vice President at Glassman-Oliver. Dr. Stockum was formerly a
staff economist and economic advisor at the Federal Trade Commission.

While these comments will suggest markedly different cost and benefit
estimates than those put forth by FDA in the economic analysis of the
proposed rule, CRN wishes to recognize the massive achievement of the
agency in grappling with this task, especially in the absence of
sufficient information regarding key variables. We believe the agency's
overall effort and the industry's attempt to respond would have been
improved by more interaction throughout this process. We again urge FDA
to consider a series of workshops to provide for further discussion and
analysis of the issues, prior to finalization of a GMP rule. This
regulation will markedly affect the ability of companies to produce
quality products while controlling costs, and it deserves further effort
on the part of all stakeholders to fully comprehend the available
alternatives.

**In this analysis, CRN has based all of its tables and analysis on the
cost and benefit information provided in the worksheets we obtained from
FDA in our FOIA request.** In some cases, the spreadsheet values differ
from the amounts shown in the *Federal Register* publication.

[Page Topic]{.underline}

3 Testing costs

5 Number of batches produced per year

6 Number of tests required per batch

6 Number of tests already being performed

7 Development of analytical methods

9 Capital expenses for renovation of facilities

9 Equipment costs

10 Consumer benefits: Reduced illness due to fewer recalls

12 Consumer benefits: Avoidance of rare catastrophic event

13 Consumer benefits: Reduced search time

15 Summary of industry costs and potential benefits as identified by FDA

16 Consumer benefits: Reduced health costs due to increased use of

beneficial dietary supplements

18 Health benefits of calcium supplementation

19 Health benefits of supplementation with B vitamins in reducing

> the risk of coronary heart disease

19 Health benefits of supplementation with long chain omega-3 fatty
acids

19 Conclusion and Recommendations

**Attachment A:** List of CRN manufacturer members and their

> products and brands

**Attachment B:** Tables showing costs and benefits of the proposed rule

**Attachment C:** Tables showing potential benefits of decreased health
costs

resulting from increased use of beneficial supplements

On August 11, 2003, CRN submitted four separate comments on the purpose
and scope of the rule, the importance of process control, legal aspects
of the proposal, and section-by-section recommendations. On July 8,
2003, CRN submitted the first comment in this series, a four-way
comparison of the proposed GMP with current food GMPs, the industry
draft published as the ANPR in 1997, and current drug GMPs.

The Council for Responsible Nutrition (CRN) is one of the leading trade
associations representing the dietary supplement industry. CRN has been
a strong supporter of Good Manufacturing Practices (GMPs) over the
years, and we have an active Regulatory Affairs Committee composed of
industry experts in dietary supplement regulation and in the technical
aspects of production processes, including GMPs. CRN's member company
experts in this arena drafted the guidelines for nutritional supplement
manufacturing practices adopted by USP over a decade ago and also
prepared the industry draft GMPs submitted to FDA in November 1995 by
CRN, joined by other industry trade associations. FDA published the
industry draft verbatim in the ANPR on dietary supplement GMPs in 1997.

CRN member companies currently include 35 manufacturers of finished
dietary supplement products and 31 manufacturers and suppliers of bulk
dietary ingredients or other components of dietary supplements, as well
as a number of associate members that provide services to the industry.
**Attachment A is a list of our manufacturer and supplier members,
together with examples of the types and brands of products they
market.** The list is designed in such a way that readers of the
electronic version can click on a company name and access its website.
CRN's membership includes some very large companies that manufacture the
leading U.S. brands of dietary supplement products, that manufacture the
store brands marketed by large food and drug chains, and that
manufacture and supply key ingredients used both in conventional foods
and in dietary supplements. Our membership also includes a number of
companies that are "small businesses" as defined by the Small Business
Administration but that also have reputations as leading quality
manufacturers of numerous products or ingredients.

CRN member companies account for a substantial fraction of the dietary
supplement market in the U.S. in terms of sales volume. Using sales data
from *Nutrition Business Journal*, we calculate that nine of the top
fifteen manufacturers and marketers of dietary supplements in the U.S.
are CRN members. These companies, plus a number of smaller CRN member
manufacturers, account for about 40% of the wholesale sales volume of
dietary supplements marketed through supermarkets, natural food stores,
drug stores, and discount department stores. Six of the top twenty
companies in direct sales (called multilevel marketing by *NBJ*) are CRN
member companies, accounting for 26% of the sales volume marketed
through that channel. Eight of the top ten vitamin ingredient suppliers
are CRN member companies, providing 71% of the sales volume for
commercial vitamins used in dietary supplements annually. Another 23
supplier members of CRN provide the industry with other key dietary
ingredients including calcium and other minerals, lutein and other
carotenoids, botanicals, omega-3 fatty acids, and specialty ingredients
such as glucosamine and chondroitin sulfate.

**TESTING COSTS**

CRN believes FDA has grossly underestimated the costs of compliance with
the proposed rule, especially the cost of testing every component of
every batch. As pointed out in our earlier comments, we believe the
exhaustive testing requirement proposed by the agency would be
excessively costly for firms of all sizes and is unnecessary in order to
ensure quality once a company has established a well-controlled
processing system. While some level of finished product testing is
always required, a properly controlled system justifies a reduced
schedule of testing of the final product. This is consistent with
well-established quality assurance theory and practice. Putting an
excessive amount of resources into testing the finished product does not
in fact constitute "good manufacturing practice." FDA appears to
recognize this fact in several places in the preamble where it is noted
that manufacturers may choose to conduct more testing of incoming
ingredients and of in-process materials rather than wait until the end
of the process to detect possible errors or defects. Building quality
into the product from the very beginning should not be an option \-- it
should be the primary focus of the GMPs. We believe the current proposal
fails to capture the essence of good manufacturing practices, and thus
does a disservice to firms of all sizes.

CRN's member companies are committed to producing quality products and
are the leading manufacturers of national brands and private label
dietary supplements. The practices observed by our member companies
[define]{.underline} "current good manufacturing practices." These
companies might reasonably have expected that they would already be in
compliance with any reasonable rule, but such is not the case with
respect to this particular proposed rule.

For purposes of computation of estimated costs, **CRN accepts FDA's
assumptions** **regarding** **the following variables:**

-   the number of control points,

-   the average number of ingredients per product,

-   the average cost per test,

-   and the percentage distribution of firms across the size range, from
    large to small to very small.

We note, however, that the range of values for the number of ingredients
per product and the cost of individual tests is large. For companies
whose products contain a large number of ingredients and for some
ingredients that are very expensive to test, much larger costs will be
incurred.

**CRN believes FDA's assumptions are grossly inaccurate for some other
variables**, including:

-   Number of batches produced by large firms;

-   Number of tests per product required by the proposed rule; and

-   Percentage of required tests currently being performed.

The mischaracterization of these three variables causes FDA to severely
understate the industry cost of compliance with the agency's proposed
testing requirements. **CRN's estimate of testing costs is 10 times as
high as FDA's**, when based on revised estimates for these three
variables derived from the experience of our large member companies.
CRN's estimate for finished product testing is \$245 million, compared
to FDA's estimate of \$24 million. Further discussion of each variable
appears below. For reference, **Table 1** reproduces FDA's estimate of
testing costs, showing the calculations and assumptions upon which the
estimate is based.

FDA's assumptions lead to an estimated total testing cost of about \$24
million for all firms. Only \$702,470 of this (about 3% of the total)
represents additional testing that may be required for large firms.
FDA's estimates do not include any in-process testing, which the rule
would clearly require. In particular, the agency's analysis suggests
that an average of 2.5 in-process tests per batch are likely to be
needed, at critical control points. Also, FDA's spreadsheets provided in
response to our FOIA request show that additional testing may be needed
for an average of 2.5 components of herbal products and 7.5 components
of vitamin products. FDA's estimates do not include costs for these
tests, and these numbers do not clearly match any of the estimates
regarding component testing or defect testing provided in the text of
the *Federal Register* publication.

**NUMBER OF BATCHES PRODUCED PER YEAR**

FDA estimates that large firms product an average of 309 batches per
year. This estimate is implausibly low and suggests that the FDA survey
did not achieve a representative sample, at least for large firms (14
responses). Moreover, it is illogical that the distribution of the
number of batches per firm is 309, 554, and 223, for large, small and
very small firms, respectively. Logic would suggest that large firms
would be expected to produce many more batches than small firms. This is
further supported by industry sales data. FDA estimates that about 6% of
firms in this industry are "large," and data from *Nutrition Business
Journal* indicate that the top 6% of firms produce 79% of the industry
sales volume through mass market and natural food channels, not
including direct sellers and ingredient suppliers. The number of batches
produced by such firms should also be large. According to the FDA
estimate, large firms would account for less than 5% of the total number
of batches produced. CRN does not believe this is a credible estimate.

CRN surveyed its member companies in an attempt to provide FDA with a
more appropriate basis for its calculations. Many companies were
reluctant to provide information directly relating to volume of
production, even on a confidential basis, but seven large firms did
provide relevant detail. Among those seven leading firms, the **number
of batches of finished products manufactured per year is in the range of
2000 to 6,700, with an average of 3,915.**

If the CRN figures and the FDA estimates are taken to represent the
upper range and the lower range of the universe of "large" firms, then
averaging these two values will provide a more realistic estimate of the
number of batches of dietary supplements produced per year by large
companies in the dietary supplement industry. As shown in **Table 2,**
we estimate the number of batches produced by large firms to be 2,112
per year, accounting for 25% of all the batches of finished product
manufactured by the industry \-- a more reasonable estimate than FDA's
value of five percent, but still possibly low.

**Table 3** shows the effect on the cost estimates of adjusting the
number of batches produced by large firms, by averaging the values
obtained from FDA's survey data and CRN's survey data. Applying FDA's
cost calculations to this larger number of batches increases the
estimate of costs for large firms by almost 6-fold.

**NUMBER OF TESTS REQUIRED PER BATCH**

FDA's cost estimates are based on the assumption that only two
ingredient tests are required per finished vitamin product and only 2.4
ingredient tests are required per finished herbal product. CRN questions
these estimates. CRN's member companies indicate that a typical
multivitamin with minerals will require at least 8 separate tests and
could require as many as 16 separate assays, depending on the specific
nutrients present. Although some test methodologies are capable of
analyzing multiple nutrients at one time, others require separate
analysis, and combined analysis is not the approved AOAC methodology. In
addition to tests for dietary ingredients, testing will be required for
other components of dietary supplements, for potential defects including
heavy metals and microbiological quality when appropriate, and for
physical specifications including hardness, thickness, disintegration
time, and in some cases dissolution time. Many dietary supplements
contain as many non-dietary ingredients as dietary ingredients.

One large member company indicated that for a typical multivitamin
product with minerals, 27 separate tests would need to be performed in
order to analyze the product for all the essential vitamins and minerals
plus physical and microbiological characteristics. This is true even
though some tests are capable of detecting or quantifying multiple water
soluble B vitamins, fat soluble vitamins, or minerals.

In later tables, especially in **Table 8**, CRN assumes that an average
of 6 tests would be required for vitamin and mineral dietary ingredients
(recognizing that many products contain only one or a few nutrients),
and an average of 2.4 tests would be required for herbal dietary
ingredients. Herbal products would also require an average of one test
for solvents. In addition, for all types of products, an average of 3
tests would be required for other components, plus 2.5 in-process tests,
plus 3 tests of the final batch for quality characteristics including
potential defects, purity, or strength. This amounts to an average
testing load of 14.5 tests for vitamin and mineral products or 11.9
tests for herbal products.

**NUMBER OF TESTS ALREADY BEING PERFORMED**

The FDA survey asked whether firms were currently testing products. FDA
indicates that 84% of large firms do conduct tests and that 90% of the
batches produced by those firms are tested. Multiplying 84% by 90%, FDA
concludes that 76% of the batches produced by large firms are already
being tested sufficiently and that no additional costs for those batches
will be incurred. Using the same approach for small and very small
firms, FDA concludes that 58% and 34% of the batches produced by such
firms, respectively, are already being tested and presumably will
require no additional testing. CRN does not believe any of these
assertions are correct.

When FDA says 84% of large firms do conduct tests, citing the survey,
the agency combines the 73% that said they do testing with 11% who said
the question was not applicable or failed to answer the question at all.
CRN believes it would be more appropriate to count these 11% as firms
that do [not]{.underline} test, and to count as positive responses only
those firms that actually responded "yes" to the question. Multiplying
this value (73%) by the 90% of products tested, CRN calculates that
large firms test 66% of the finished product, rather than the 76%
calculated by FDA. Similarly, we calculate that small and very small
firms are currently testing 58% and 28% of finished product,
respectively. **Table 4** illustrates the calculations provided by FDA,
based on the results of the survey, and those suggested by CRN, based on
the same survey.

CRN's calculations, based on the FDA survey, indicate that 34% of the
batches produced by large firms are not currently being tested. This
figure is 40% greater than FDA's estimate of 24% of large firms not
already testing finished products, and accordingly the cost of
additional testing for large firms would increase by 40%. See **Table
5** for these calculations. The additional testing required for very
small firms would also increase. This increase is captured in our
summary **Table 8.**

Even large firms that are testing 90% of their products are unlikely to
be performing the exhaustive level of testing required by the proposed
rule, namely testing every component of every batch of finished product.
Thus, a substantial volume of additional testing is likely to be
required even for such firms. While leading companies do perform
finished-product testing to confirm that their quality procedures are
operating effectively, virtually no company tests every component of
every batch. To do so would be prohibitively expensive as well as
unnecessary, since a well-controlled process can reliably ensure quality
while enabling a firm to conduct a reduced level of testing. This most
commonly includes testing some specifications in every batch and testing
other specifications on a periodic basis. We estimate that full
compliance with the rule as proposed would require at least 40% more
testing than is currently being done on finished batches which are
tested, and this of course will increase costs. As shown in **Table 6,**
this implies that only 71% of the testing that would be required by the
rule is currently being done for finished products. Some leading
companies indicated that even a greater percentage of additional testing
would be required by the FDA proposal. **Table 7** shows the cost
implication of the additional testing requirement for large firms.

**Table 8** summarizes CRN's calculations of additional testing costs
that would be required under the rule as currently proposed. We estimate
that testing costs for firms of all sizes would be almost \$245 million,
compared to FDA's estimate of \$24 million. This incorporates our
earlier estimates of the number of tests required by the proposed rule,
including tests for dietary ingredients, other components, tests of
quality, purity and strength, in-process tests, and herb solvent tests.

**DEVELOPMENT OF ANALYTICAL METHODS**

FDA's economic analysis does not include an estimate for the cost of
developing methods of analysis. Methods development has been an
important focus of industry effort for a number of years, and such
efforts are costly.

The U.S. Pharmacopeia (USP) has for over a hundred and fifty years been
developing methods for nutrients and botanicals used for therapeutic
purposes and is the recognized authority on analytical methods for
drugs. Beginning in 1985, USP launched an initiative to develop quality
standards and analytical methods for nutritional supplements (primarily
containing vitamins and minerals), and in 1995 that effort was expanded
to include botanical dietary supplements. In the process of these
activities, it has been recognized that significant methodological
challenges exist even with respect to analyzing some nutrients (such as
folic acid), let alone with respect to botanical and specialty
ingredients. The American Herbal Pharmacopeia has also been compiling
botanical monographs that address methods of analysis, among other
topics. These ongoing activities emphasize the widespread recognition of
the fact that there is a continuing need for methods development in this
industry.

Recognizing a need for more industry involvement in method development,
the INA/MVP testing initiative was developed, originally under the
sponsorship of Industrial Laboratories. The initiative has recently been
incorporated into the activities of NSF International, as a feature of
NSF's dietary supplement certification program. With substantial
industry involvement, laboratory development costs were kept to a
minimum but still amounted to \$15,000 to \$20,000 for each of 22
methods developed so far in this program, with two or three labs
cooperating in the validation of each method.

AOAC is the recognized authority for analytical methodologies for foods.
Numerous AOAC methods currently exist for vitamins and minerals, but not
all of these have been validated for the types of matrices typical of
dietary supplement products. The number of AOAC methods that currently
exist for botanical ingredients is small. Recognizing the need for
additional methods development, Congress recently appropriated funds for
the Office of Dietary Supplements (ODS) to invest in such activities.
ODS has contracted with AOAC to develop 20 new methods over the next
five years, and a budget of \$1 million has been allocated to this
effort, amounting to an average of \$50,000 per method. The methods to
be developed will be single-laboratory-validated methods. They will not
be fully validated through multilaboratory testing, as is usual for AOAC
methods, although such validation is desirable and may be undertaken at
a future time. AOAC has convened a working group of industry and
government interested parties to assist in this effort, including the
preparation of a priority list of methods to be developed. That priority
list currently includes twenty (20) ingredients, and participants
indicated at a recent workshop that at least five times this many could
be immediately identified, if more resources were available \-- and
these would cover only the most commonly utilized ingredients, not the
full number of ingredients likely in need of method development.

Thus, CRN believes the estimated cost of the proposed rule should
include a figure for the investment required to develop scientifically
valid methods of analysis for numerous ingredients. At a minimum, we
believe this figure should include the cost of 100 methods at a minimum
cost of \$20,000 each, or a total of \$2 million. The actual cost of
method development is, we believe, more likely to be in the range of
\$50,000 for each test, or twice that amount if the method were to be
fully validated by multiple laboratories. Thus, an estimate of \$2
million for method development would be highly conservative.

**CAPITAL EXPENSES FOR RENOVATION OF FACILITIES**

FDA indicates that the capital costs for physical plant redesign would
be about \$50 per square foot, and that establishments might have to
renovate 0 to 20 percent of the physical plant, with 10% being the most
likely value. Based on FDA's survey results regarding the size of
various plants and assuming that 10% of the plant would require
renovation, these figures result in costs of over \$89,000 per company
for very small firms and more than 260,000 for small and large firms.
**Table 9** shows the calculation of these costs, which CRN believes
will total over \$600 million for the industry as a whole, as compared
to FDA's estimate of \$45 million.

The reason FDA's estimate of capital costs is so low is that the agency
applies a reduction factor for which no justification is provided. The
reduction factor assumes that only 18% of very small firms, 10% of small
firms, and 1% of large firms will actually need any capital improvements
to the facility. Based on information provided by our member companies,
CRN believes application of the reduction factor is inappropriate, since
most firms believe they will in fact need to improve their facilities if
the rule is finalized as proposed. Therefore, CRN believes FDA's
estimate that most facilities will need to renovate about 10% of their
physical plant is approximately accurate and should be included in the
cost estimates, without a reduction factor.

One key requirement of the proposed rule that may necessitate
modification of facilities is the provision mandating "smooth, hard
surfaces" on all floors, walls, and ceilings. There is no precedent for
this requirement in food GMPs, and the only precedent we can identify
even in drug GMPs is a provision applicable to aseptic processing of
some drugs including injectable products. There is no need for smooth,
hard surfaces on all ceilings in a manufacturing facility and thus
virtually no company will have such surfaces throughout the plant. If
FDA persists in this requirement, capital costs will naturally be
affected.

**EQUIPMENT COSTS**

FDA estimates that the cost of new equipment needed to comply with the
proposed rule would be zero to \$1000, with \$100 the most likely. The
agency assumes these costs would increase as a function of the size of
the physical plant and would therefore be three times as great for small
companies and 20 times as great for large companies. FDA's total
estimated equipment expense is therefore \$100 for very small companies,
\$300 for small companies, and \$2,000 for large companies. These
estimates are frankly laughable. We found it difficult to identify
examples of any equipment relevant to quality assurance that could be
purchased at such a low cost. Latex gloves, filter papers, and some
glassware fell into this category.

A large company that already has a testing infrastructure but needs to
expand its capacity may reasonably expect to incur expenses of about
\$240,000. This would cover the addition of two HPLCs at a cost of
\$75,000 each, an ICP at a cost of \$50,000, and a GC at a cost of
\$40,000. This estimate does not include extra staffing, service
agreements and repairs (about 5 to 10% of the cost of equipment),
supplies necessary to operate the equipment, and reference standards.

It should be noted that equipment costs may bear especially heavily on
very small companies, who may not currently have well-equipped
laboratories. Thus, FDA's assumption that costs will be lower for very
small companies may be directly contrary to the reality. In fact, very
small companies will face larger costs if they need to establish a
laboratory and do not currently have a testing infrastructure. The
equipment cost alone for a new laboratory is estimated to be
approximately \$300,000 for major equipment such as an HPLC, GC, AA/ICP,
UV, FTIR, a dissolution apparatus, and equipment needed for for
performing microbiological tests. In addition, about \$20,000 in basic
laboratory equipment and supplies would be needed such as glassware,
chemicals, standards, hotplates and stirrers, pH meters, a fume hood, a
furnace, and balances.

**CONSUMER BENEFITS: REDUCED ILLNESS DUE TO FEWER RECALLS**

CRN analyzed the FDA weekly enforcement reports for the decade of the
1990's. The attached **Table 10** shows CRN's compilation of Class I and
Class II recalls for dietary supplements, conventional foods, and drugs
from 1990 through 1999, based on FDA's weekly enforcement reports for
this period. For this period, FDA weekly enforcement reports show a
total of 2542 Class I and Class II recalls for conventional foods,
dietary supplements, and drugs. Of this total, dietary supplements
account for only 52. Drugs account for 997, and conventional foods
account for 1493. As a function of sales volume, the rate of recalls for
dietary supplements is comparable to the rate of recalls for
conventional foods. For both categories, there are about 0.3 recalls per
year per billion dollars in sales volume (based on a current market size
of approximately \$18 billion for dietary supplements and approximately
\$500 billion for conventional foods). This illustrates that these two
categories of foods have a similar record for product quality and
safety, to the extent that recalls are a reflection of these
characteristics. (In actual fact, these calculations underestimate the
number of recalls of conventional foods, since they include only FDA
recalls and do not include recalls of foods regulated by the U.S.
Department of Agriculture.) Drugs have a higher rate of recalls,
amounting to about 0.7 recalls per billion dollars in sales volume
(based on a current market size of approximately \$145 billion). Thus,
it is evident that stringent GMPs (such as drug GMPs) do not of
themselves result in a dramatically reduced rate of recalls.

FDA's preamble text indicates that there were, on average, 13 dietary
supplement recalls per year during the 10-year period from 1990 through
1999, or an implied total of 130. This is more than twice the number
identified by CRN for the same period. **Table 11** shows the number of
Class I and Class II recalls of dietary supplements CRN identified from
FDA's weekly enforcement reports for the period from 1990 through 1999.
We identified only 52 Class I and Class II recalls for dietary
supplements during this period.

One possible reason for this discrepancy is that FDA may be counting
each separate item covered by a given recall as a separate event. For
example, in the FDA tabulation of recalls, provided in Table 8 of the
*Federal Register* publication of the proposed rule, FDA lists 41 Class
II recalls relating to EMS. Based on new background information we
recently received from FDA under our FOIA request, this appears to have
been an error. It seems that several lines of information were omitted
from FDA's Table 8 and that these 41 Class II EMS recalls actually
should have been identified as Class II recalls of dietary supplements
with excessive lead content. In CRN's analysis of FDA's weekly
enforcement reports, we identified only 11 class II recalls of dietary
supplements relating to excessive lead content. (For comparison, we
identified 45 class I and class II recalls of conventional foods due to
excessive lead content during this same period.) Some of the dietary
supplement recalls covered more than one product distributed by a given
manufacturer. Two of the recalls covered 5 products each, one covered 9
products, and one covered 10 products. Only by counting these as
separate recalls can we approach FDA's reported total of 41 recalls for
dietary supplements due to excessive lead content. If this was the
agency's approach to counting dietary supplement recalls, we question
its appropriateness.

Of the recalls tabulated by FDA, 33 are attributed to the recalls
involving dietary supplements that were intended to contain plantain
leaf but that were contaminated with leaves from the plant *Digitalis
lanata.* We have examined the FDA weekly recall reports for the period
1990 through 1999, and we can only identify 13 digitalis recalls during
this period. We believe the agency may have counted each separate item
mentioned in each of the 13 recalls, to reach the total of 33 reported
in the table. For example, one recall for "Chomper" lists five sizes or
varieties of the Chomper product covered by the recall. This item is
listed as one recall in the FDA weekly enforcement report, and we count
it as one recall in our tabulation of recalls. Unless FDA counted this
as five recalls for purposes of its tabulation, and did the same for the
other plantain recalls, we cannot understand how the agency arrived at a
total of 33 recalls relating to plantain/digitalis. Counting each
separate item covered by a given recall as a separate event does not
appear to us to be appropriate.

Logically, we would suggest that the plantain recall should be treated
as a single event. Only two adverse events were reported in association
with the plantain recall, including the one that triggered discovery of
the problem. There was very substantial publicity at the time of this
recall, and a number of related FDA consumer warnings. The FDA
announcements and media attention should have led to essentially full
reporting of any adverse events experienced by other consumers using the
products. Thus, whatever the base number of plantain recalls FDA chooses
to utilize in this analysis, it would not be appropriate to apply the
100-fold multiplication because the assumption of under-reporting in
this case is not sound.

If the true number of Class I and Class II dietary supplement recalls
for the period 1990 through 1999 is 52 as CRN calculates rather than 130
as indicated by FDA, the cost implications of those recalls and thus the
benefit of avoiding those illnesses would be drastically lowered, even
if we were to accept FDA's assumptions about the 100-fold relationship
between the number of recalls and the number of potential illnesses. In
**Table 12** we show the calculation of the weighted average cost of
illness due to Class I and Class II recalls, as tabulated by FDA.

In **Table 13** we show FDA's calculation of the cost of illness due to
recalls, as compared to the CRN calculation based on the number of
recalls we identified from the FDA weekly enforcement reports. The
smaller number of recalls naturally leads to a smaller estimate of the
annual cost of illness associated with those recalls: \$14 million as
compared to FDA's estimate of \$39 million.

FDA cites a reference by Walker for the agency's assumption that each
illness due to a recall is a proxy for 100 unreported illnesses.
However, the same reference recognizes that under-reporting is less
likely for serious illnesses than for minor illnesses. The third column
of **Table 13** illustrates the effect of assuming a reporting rate of
10% rather than 1%, at least for the deaths included in the FDA
analysis. This assumption would reduce the cost of illness associated
with recalls to \$6 million, when applied to the CRN values in column
two. When applied to the FDA values in column one, this assumption would
also reduce the cost of illness associated with recalls, although this
calculation is not shown in the table.

In the analysis of economic impacts, FDA assumes that new GMPs will
reduce human error to zero and says there will be no more recalls of
dietary supplements once these regulations are in place. This is
unrealistic. In all FDA-regulated product categories, recalls occur with
regularity for a variety of reasons. GMPs will not totally eliminate
human error. The current number of recalls appears to be entirely
comparable, per billion dollars in sales, with the number of recalls
occurring in the conventional food industry, and CRN believes it would
not be realistic to project a very large change as a result of new GMPs.
If the expected reduction in recalls is estimated to be 50%, that would
halve FDA's estimate of the benefits to be obtained due to fewer
illnesses related to recalled products. Based on the ongoing recall
experience relating to conventional foods and pharmaceutical products,
we believe such an estimate would be more realistic but still perhaps
optimistic. **Table 13** shows the effect of a 50% projected reduction
in the cost of illness due to recalls, rather than FDA's estimate of a
100% reduction.

**CONSUMER BENEFITS: AVOIDANCE OF RARE CATASTROPHIC EVENT**

A large fraction of FDA's estimated benefit from the GMP rule is
attributable to avoiding rare catastrophic events such as the outbreak
of eosinophilia myalgia syndrome (EMS) due to a change in manufacturing
on the part of one manufacturer of the amino acid tryptophan. The
tryptophan incident occurred in 1989, and FDA uses it to postulate a
30-year cycle of potential catastrophic events due to dietary
supplements. Dietary supplements have been a fixture in the American
marketplace at least since at least the 1920's, when vitamins first
became commercially available as purified components, so a longer
periodicity could just as easily be justified. In **Table 14** we
suggest a periodicity of 70 years rather than 30 years, with an
accordingly reduced estimate of prorated annual costs of illness.

FDA comments at 68 FR 12232, "The benefits attributable to this proposed
rule from preventing a rare catastrophic event are highly uncertain. We
do not know if such event would, in the absence of the proposed
regulation, ever occur again."

CRN points out, in addition, that it is highly uncertain whether these
or any other GMPs would have prevented the EMS outbreak. The amount of
the purported impurity in the tryptophan that was associated with the
outbreak was extremely small. No one would have been able to predict
that such a small change in the characteristics of the ingredient could
have a large effect. Since the identity of the problem component was
unknown, no one would have tested for it. Since the quantity of the
problem component was so small, it did not adversely impact the
acceptability profile of the bulk ingredient, which was said to conform
to USP criteria for tryptophan. It is also relevant that some of the
tryptophan involved in the outbreak was sold in Europe, where it was
solely used in prescription drugs subject to stringent GMPs. A
substantial number of the EMS cases identified by the Centers for
Disease Control and Prevention (CDC) were associated with the use of
such pharmaceutical products. Thus, we believe it is questionable
whether improved GMPs (even pharmaceutical GMPs) would have or could
have prevented the EMS outbreak.

**CONSUMER BENEFITS: REDUCED SEARCH TIME**

FDA reasons that increased consumer assurance of quality due to the GMPs
could result in a reduction in the time required for consumers to search
for nutritional supplements. Accordingly, FDA hypothesizes that the
value of the increased assurance of quality resulting from GMPs can be
proxied by the value of the reduction in consumer shopping time.

This approach suffers from fundamental analytical flaws as well as
weaknesses in the values used for certain critical variables in the
computation. Also, FDA's analysis appears to proceed from the assumption
that dietary supplements are not currently covered by any GMPs, which is
not the case. Dietary supplements in fact are already covered by food
GMPs and CRN's member companies are subject to inspection by FDA and
state field officers, using food GMPs as the standard against which
their procedures are evaluated.

To the extent that new dietary supplement GMPs increase consumer
confidence in the industry\'s products, CRN contends that the primary
benefit will result from greater use of beneficial dietary supplements.
Increased use of dietary supplements would lead to improved health and
resultant savings in health costs. While it is possible that some search
cost savings might occur, these savings would be trivial relative to
health cost savings.

In order for either of these benefits (savings in health costs or search
costs) to occur, consumers must be informed about the GMPs, and must
gain confidence that these GMPs will assure product quality. The FDA
does not indicate what information will be disseminated to consumers or
how it will be disseminated. Indeed, the preamble indicates that the
agency would specifically prohibit companies from highlighting their
compliance with GMPs in product labeling. It is far from clear that
consumers will be broadly informed about these changes in manufacturing
standards, or what percentage of those who do learn about the GMPs will
interpret the information as indicating higher product quality. Yet the
FDA\'s computation of search cost savings implicitly assumes that all
consumers will be informed about the GMPs and will interpret the FDA\'s
action as resulting in increased industry quality. If the benefits
contemplated by FDA can only be realized if consumers are educated about
the regulatory changes that have occurred, the agency should make
efforts to assure that the information reaches consumers appropriately.

FDA's computations regarding search costs do not include a discount
factor based on the percentage of consumers who become informed about
the regulation and interpret it as intended. While it seems clear that a
significant proportion of consumers would not become informed or would
not interpret the information appropriately, we do not have information
regarding the appropriate discount factor. In any event, the estimated
search cost savings are overstated to the degree that no discount factor
is applied.

FDA\'s models multiply the estimated total shopping time by the
estimated percent of that time spent \"searching\" (70%), then multiply
the result by the estimated percent of time spent searching for
\"quality\" (20%), then assume that this time spent shopping for
"quality" would be reduced by 33% by the GMPs. No reference is offered
for either of the first two assumptions (in either the *Federal
Register* publication or the FOIA response), and the reference for the
third one offers highly limited support. The use of these three
variables lends very little statistical confidence to the conclusions
drawn by these models. Indeed, FDA notes at the top of 68 FR 12234 that
the hypothetical search time reduction is merely a proxy for improved
quality, adding, "We anticipate little or no change in aggregate
shopping time for dietary supplements."

Consumer attitudes about \"quality\" (FDA uses this term without any
qualifier or definition throughout) clearly include concepts unrelated
to the GMPs. For example, a shopper contemplating purchasing a
supplement to increase energy may spend a considerable amount of time
attempting to assess the relative effectiveness of the numerous products
offered. This is a search for product \"quality\" but not the type of
quality addressed by the GMPs.

Consumers currently have only a limited ability to draw inferences about
manufacturing quality and thus likely spend very little time performing
the futile search endeavor emphasized in the three models. While the
GMPs arguably could raise the lower bound of the quality range in this
industry, this cannot have much of an effect on a variable that is
trivial in the first place.

This is not to say that consumers ignore quality in the dietary
supplement industry, only that their quality searches must emphasize
variables about which they can logically draw inferences, which largely
are ones not affected by the GMPs. One means of assessing quality that
consumers may undertake is to look for reputable brand names. In this
context the FDA notes (68 FR 12233, with references to E25, E26 and E27)
that consumers spend time assessing \"the large variation in product
quality\" for various products. This effort is aimed at comparing
relative quality across alternative brands and thus largely would not be
affected by the GMPs.

Consumers may conclude that health risks will be lessened by the GMPs.
However, FDA\'s stated intent for the search cost models is to generate
a proxy for the value to consumers of increased quality. To the extent
that it reflects perceived reduced health risks, this proxy double
counts values already included in the reduced cost of illness associated
with recalls.

Thus, we find the purported link between search costs and the proposed
GMPs to be a highly dubious one, both from a logical analytical
standpoint and as a computational approach employed by FDA in estimating
savings, and we do not count reduced search costs as a benefit of the
rule in our analysis. CRN is disappointed that FDA has resorted to such
thin support as an important component of its justification for such a
significant and costly industry regulation. We believe the health
benefits of increased supplement use, discussed in the next section, may
provide more substantial support for the proposed GMPs.

**SUMMARY OF INDUSTRY COSTS AND POTENTIAL BENEFITS AS IDENTIFIED BY
FDA**

As shown in **Table 15,** CRN's calculations show markedly increased
costs, compared to FDA's analysis. Also, we question some of the
benefits relied upon by the agency to offset those costs. As shown later
in this document, however, we propose another benefit that FDA could
consider, in terms of reducing consumer health costs through improved
nutrition and disease prevention. These benefits could accrue to
consumers if they have increased confidence in dietary supplements as a
result of the new GMPs and accordingly make more use of beneficial
dietary supplements.

FDA's estimated benefit \$ 216.6 million

CRN's estimated benefit \$ 34.0 million

FDA's estimated annual costs \$ 79.4 million

CRN's estimated annual costs \$ 300.6 million

FDA's one-time costs \$ 54.5 million

CRN's one-time costs \$ 629.0 million

The agency's calculations result in a net benefit of \$82.8 million in
the first year and \$137.3 million in subsequent years. CRN's
calculations result in a negative benefit of (\$895.7 million) in the
first year and (\$266.6 million) in subsequent years.

**CONSUMER BENEFITS: REDUCED HEALTH COSTS DUE TO INCREASED USE OF
BENEFICIAL DIETARY SUPPLEMENTS**

CRN is cognizant of the need to arrive at a balance of costs and
benefits that are likely to be associated with new GMPs. FDA's
calculated benefits are all directed at avoiding problems presumably
associated with dietary supplements and do not take into consideration
any positive health benefits from increased use of supplements. We
believe the implementation of new, stronger GMPs for dietary supplements
will raise the overall quality of products available to consumers and
thus engender confidence in the industry, thereby resulting in social
benefits. If this effect is significant, sales of dietary supplements
should increase, and some consumers who were near the margin of
purchasing supplements would be induced to buy them. Others who may
currently use supplements only occasionally may be induced to purchase
then more frequently. Consumers who are already regular supplement users
may decide to increase the number of beneficial products they
incorporate into their daily health regimen. The extent to which these
changes occur may depend importantly on whether improved quality and
thus stronger consumer confidence is achieved without substantial
increases in the price of dietary supplements available to the public.

Increased use of beneficial dietary supplements would result in social
benefits in the form of improved health for consumers. If this effect
were substantial, health costs would fall and other related benefits
would accrue, including improved quality of life (e.g., for an elderly
person who takes calcium supplements and does not suffer a hip
fracture). FDA does not acknowledge this important category of social
benefits in its rulemaking on GMPs for dietary supplements. Yet a
considerable body of evidence supports the conclusion that the health
benefits of supplement usage can be very significant. CRN's 2002
publication *Benefits of Nutritional Supplements* provides a useful
overview. (Dickinson, 2002) While numerous scientific studies establish
the benefits of supplementation with specific nutrients or other dietary
supplements, most of these do not lend themselves to quantification for
the purpose of cost-benefit analysis, and few authors actually undertake
a formal economic analysis of costs and benefits. We will rely on a few
conservatively selected examples to make the point that large benefits
in disease reduction and accompanying reductions in health costs are
achievable through even small increments in appropriate supplement use
by the relevant target populations.

Some of CRN's member companies are currently engaged in research on the
potential health care cost savings that may be achieved through optimal
use of beneficial dietary supplements, through reduction of disease
risk. Unfortunately, these efforts are not yet complete and some of the
information will not be made available until it is accepted for
publication in a peer-reviewed journal \-- a process which takes
considerable time. If new data becomes available while this GMP rule is
still under consideration, we will provide it to the agency.

It has long been a goal of public health policymakers to gain control
over escalating health care costs by improving overall health and
therefore reducing the risk of disease, especially the chronic diseases
that contribute so heavily to current health care costs. Dr. Michael
McGinnis of the Robert Wood Johnson Foundation and Dr. Nancy Ernst of
the National Institutes of Health recently observed that Americans
suffer a heavy burden of disease that is potentially preventable and
predicted that healthier dietary practices could save \$71 billion per
year in medical costs, lost productivity, and the value of lives lost
prematurely to major chronic diseases. (McGinnis & Ernst, 2001)

Dr. Jeffrey Blumberg of the School of Nutrition Science and Policy at
Tufts University has estimated the potential health care cost savings
that could be realized if improved dietary practices were adopted and if
those improved habits delayed the onset of cardiovascular disease,
strokes, and hip fracture by 5 years. He wrote: "A 5-yr delay in the
onset of cardiovascular disease could save about \$69 billion annually.
A delay in the onset of strokes by 5 yr would be associated with annual
savings of \$15 billion. A 5-yr delay in the occurrence of hip fracture
annually could cut the number of events by 140,000 each year and save an
estimated \$5 billion annually." (Blumberg 1997) Delaying the onset of
these three conditions alone could thus potentially result in a health
care cost savings of \$89 billion every year. Some specific nutrients
including B vitamins, omega-3 fatty acids, and calcium have been shown
to reduce the risk of cardiovascular disease, strokes, and hip fracture.
Other nutrients that have been shown to have protective effects on other
conditions include antioxidants (vitamin C, vitamin E, lutein) for
reducing the risk of cataracts and age-related macular degeneration, but
we have no cost/benefit data upon which to base economic estimates for
these conditions at this time.

If stronger GMPs increase consumer confidence in dietary supplements and
therefore lead to an increase in the usage of products with recognized
health benefits, such as multivitamins and calcium and omega-3 fatty
acids, then one could predict that more consumers would obtain those
health benefits and experience a reduction in chronic disease risk. The
resulting health cost savings could potentially be included in FDA's
calculation of the benefits of the GMP rule. In this discussion, CRN
will focus solely on nutrient/disease relationships that FDA has already
evaluated and for which FDA has already approved an NLEA health claim or
a qualified health claim. Of course, there are other benefits that may
accrue from increased supplementation with various nutrients, so
limiting our evaluation to those for which health claims or qualified
health claims are permitted will result in a highly conservative
estimate. The three examples we will offer relate to:

-   Calcium supplementation to reduce the risk of osteoporosis;

-   B vitamin supplementation to reduce the risk of cardiovascular
    disease; and

-   Supplementation with long chain omega-3 fatty acids to reduce the
    risk of coronary heart disease.

In each case, our calculations will be drawn primarily from a single
article and will estimate the health cost savings that could result if
**[one percent of the target population]{.underline}** were to begin
using the relevant supplement on a regular basis. The target population
is women age 75 and over for osteoporosis, men over 45 for the B vitamin
benefit, and people with a history of heart disease for the omega-3
fatty acid benefit.

Using very conservative estimates, we estimate a total health benefit
from reduced risk in the amount of about \$659.6 million from reduced
disease risk if 1% of the target population for each of the above
conditions were to begin using the relevant supplement on a regular
basis (Attachment C, Table 1). Thus the benefit is easily calculated
based on various assumptions about the potential fraction of the
population that could be motivated to use the supplement. If 5% of each
target population started using the supplement, then the potential
benefit would be 5 times as high, or \$3.3 billion per year.

**HEALTH BENEFITS OF CALCIUM SUPPLEMENTATION**

More than six million adults in the United States have osteoporosis,
leading to nearly 300,000 hip fractures annually, at a cost to the
health care system of almost \$9 billion per year. Several consensus
conferences convened by the National Institutes of Health have
recommended high calcium intakes (1500 mg per day) for postmenopausal
women who are not taking estrogen replacement therapy.

Bendich and co-workers have analyzed the potential health cost savings
that could be realized in the limited population of women 75 years of
age and older, if they took supplements of 1200 mg calcium and thus
avoided hospitalization for hip fracture. (Bendich 1999) The estimates
we have incorporated from this article are highly conservative, since
they consider only women 75 and older and they consider only hip
fracture, although decreasing the risk of osteoporosis would also reduce
other types of fracture. Also, these estimates include only direct
medical care costs incurred in the hospital and in post-hospital care.

Bendich and coauthors conclude that among women 75 and older, it would
be possible to realize a 46% reduction in hospitalizations for hip
fracture, resulting in 83,589 fewer hospitalizations and a savings of
\$1.65 billion. Backing out the cost of supplementation with 1200 mg
calcium for the 9.4 million women in this age group, the potential cost
benefit nets out at \$1.2 billion. If even **[one percent]{.underline}**
of the women in this age group undertook calcium supplementation as a
result of increase confidence in the products due to new GMPs and
avoided hip fracture, the potential benefit would be one percent of that
total, or \$12 million per year (Attachment C, Table 2). If we were to
conservatively estimate that 5% of women 75 and older might be motivated
to begin calcium supplementation, if new GMPs caused them to have
greater confidence in the product category, the benefit in health costs
averted for hip fracture would be \$60 million per year.

**HEALTH BENEFITS OF B VITAMINS IN REDUCING THE RISK OF CORONARY HEART
DISEASE**

A high homocysteine level has been identified as a risk factor for
coronary heart disease. Increased intake of B vitamins including folic
acid reduces homocysteine levels, and people with lower homocysteine
levels have a reduced risk of heart disease. Tice and co-workers
recently evaluated the cost effectiveness of grain fortification with
folic acid and of additional vitamin supplementation with folic acid and
vitamin B-12 for heart disease prevention. (Tice 2001) The most
cost-effective approach, beyond the existing grain fortification
program, was found to be supplementing men 45 years of age and over with
folic acid and vitamin B-12. The calculated benefit is shown in
Attachment C, Table 2. It amounts to a health benefit of \$59.9 million
per year for every one percent of men 45 years of age and over
(Attachment C, Table 3). To illustrate the calculations that could be
drawn from this information, it implies that if 5% of men in this age
group adopted regular supplementation with folic acid and B-12, the
potential benefit could be five times as large, or \$300 million per
year.

**HEALTH BENEFITS OF SUPPLEMENTATION WITH LONG CHAIN**

**OMEGA-3 FATTY ACIDS**

The GISSI study observed a significant reduction in risk of
cardiovascular death in men who had already experienced a myocardial
infarction and who subsequently received supplementation with long chain
omega-3 fatty acids. (GISSI 1999) The calculation of the benefit shows a
potential gain of \$587.3 million dollars per year for every one percent
of MI survivors who adopts regular supplementation with omega-3 fatty
acids EPA and DHA (Attachment C, Table 4). If five percent of this
target population adopted such supplementation as a result of improved
confidence in dietary supplements due to stronger GMPs, this figure
would reach almost \$3 billion per year.

**CRN CONCLUSIONS AND RECOMMENDATIONS**

CRN supports the need for improved dietary supplement GMPs, but we find
the FDA's current proposal to be unbalanced in terms of cost and benefit
due in part to the heavy focus on exhaustive end-product testing rather
than on building quality into the product through rigorous process
control. A well-controlled process justifies a decreased testing burden
with respect to the finished product, but such a system cannot be
implemented without extensive written procedures to ensure that the
process remains the same over time and that the system performs
consistently in the hands of many different operators. Increased
consumer confidence in dietary supplements can and should result in
increased usage of beneficial supplements, with resulting improvements
in health and reduced risk of disease.

CRN again urges the agency to consider convening a series of workshops
to permit the industry and other stakeholders to work together with FDA
to seek an optimal approach to improving dietary supplement GMPs so that
a final rule can be promulgated and enforced in a manner that protects
consumers, enables the industry to produce quality products at a
reasonable cost, and provides FDA with the necessary framework to
appropriately regulate the myriad of companies that make up the dietary
supplement industry.

Sincerely,

![](media/image2.png){width="1.9541666666666666in"
height="0.5215277777777778in"}

Annette Dickinson, Ph.D.

President

*[References]{.underline}*

Bendich A, Leader S, Muhuri P. Supplemental calcium for the prevention
of hip fracture: potential health-economic benefits. Clinical
Therapeutics 1999; 21:1058-1072.

Bendich A, Mallick R, Leader S. Potential health economic benefits of
vitamin supplementation. Western J Med 1997; 166:306-312.

Blumberg J. Public health implications of preventive nutrition. In:
Bendich A, Deckelbaum RJ, editors. *Preventive Nutrition.* Humana Press,
Totowa, NJ, 1997.

Dickinson A. *Benefits of Nutritional Supplements.* Council for
Responsible Nutrition, Washington, D.C., 2002.

GISSI-Prevenzione Investigators. Dietary supplementation with n-3
polyunsaturated fatty acids and vitamin E after myocardial infarction:
results of the GISSI-Prevenzione trial. (Gruppo Italiano per lo Studio
della Sopravvivenza nel'Infarto miocardico.) Lancet 1999; 354:447-455.

McGinnis JM, Ernst ND. Preventive nutrition: a historic perspective and
future economic outlook. In: Bendich A, Deckelbaum RJ, editors. *Primary
and Secondary Preventive Nutrition.* Hukmana Press, Totowa, NJ, 2001.

Tice JA, Ross E, Coxson PG, Rosenberg I, Weinstein MC, Hunink MGM,
Goldman PA, Williams L, Goldman L. Cost-effectiveness of vitamin therapy
to lower plasma homocysteine levels for the prevention of coronary heart
disease: effect of grain fortification and beyond. J Am Med Assn 2001;
286:936-943.

+----------------------------------+-----------------------------------+
| # Ma                             |                                   |
| nufacturers of Finished Products |                                   |
+----------------------------------+-----------------------------------+
| # Member Company                 | # Products                        |
+----------------------------------+-----------------------------------+
| [Access Business                 | Nutrilite®, Trim Advantage®       |
| Group/Nutrilit                   |                                   |
| e](http://www.alticor.com/produc |                                   |
| ts/nutritional_supplements.html) |                                   |
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| [Accucaps Industries             | Private Label Manufacturer of     |
| Limited](http://ww               | Vitamins and Minerals, Oils,      |
| w.accucaps.com/defaultframe.htm) | Specialty Supplements, and        |
|                                  | Herbals                           |
+----------------------------------+-----------------------------------+
| ### [                            | ### Sokoja®, Azinc®, Potensium®,  |
| *Arkopharma, LLC*](http://www.ar | Arkocaps®, Memoboost®, Turbodiet® |
| kopharma.com/english/index.html) |                                   |
+----------------------------------+-----------------------------------+
| [B&C Nutritional Products,       | Private Label Manufacturer of     |
| Inc.](http://www.bcnutrit        | Vitamins and Minerals, Specialty  |
| ional.com/product_offerings.htm) | Supplements, and Herbals          |
+----------------------------------+-----------------------------------+
| [Bayer HealthCare                | One-A-Day®, Flintstones®          |
| LLC](ht                          |                                   |
| tp://www.bayer.com/en/index.php) |                                   |
+----------------------------------+-----------------------------------+
| [Bio San Laboratories            | Private Label Manufacturer of     |
| Inc.](http://www.biosan.net/)    | Vitamins and Minerals, MegaFood®, |
|                                  | DailyFoods®, Essentials®          |
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| [Enzo                            | Enzogenol®                        |
| Nutrace                          |                                   |
| uticals](http://www.enzo.co.nz/) |                                   |
+----------------------------------+-----------------------------------+
| [Experimental and Applied        | AdvantEdge®, BetaGen®, CytoVol®,  |
| Sciences, Inc.                   | EcdyMax®, Lean DynamX®, Mass      |
| (EAS)](http://www.eas.com/)      | Factor®, Muscle Drive®, Myoplex®, |
|                                  | Precision Protein®, Simply        |
|                                  | Creatine®, SimplyProtein®, Synthe |
|                                  | Vol®, Thermo DynamX®, ZMA®        |
+----------------------------------+-----------------------------------+
| [GNC                             | GNC ProPerformance®, Preventive   |
| In                               | Nutrition®, Herb Plus®, GNC       |
| corporated](http://www.gnc.com/) | Natural Brand®, Total Lean®, Mega |
|                                  | Men®, Womens Ultra Mega®, Herbal  |
|                                  | Plus®                             |
+----------------------------------+-----------------------------------+
| [GNLD                            | Carotenoid Complex®, GR^2^        |
| Inte                             | Control®                          |
| rnational](http://www.gnld.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Herbalife                       | Herbalife, Thermo Complete®,      |
| Internationa                     | Thermojetics®,                    |
| l](http://www.herbalife.com/uk/) |                                   |
+----------------------------------+-----------------------------------+
| [Jamieson Laboratories           | Mega Cal®, Vita Vim®              |
| Ltd.](h                          |                                   |
| ttp://www.jamiesonvitamins.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Kemin Consumer Care,            | Satise®                           |
| L.L.C.](http://www.kemin.com/)   |                                   |
+----------------------------------+-----------------------------------+
| [Mannatech,                      | Glycentials®, Ambrotose®,         |
| Inc.](http:                      | Phyt•Aloe®, CardioBALANCE®,       |
| //www.mannatech.com/default.asp) | ImmunoStart®, Glyco•Bears®,       |
|                                  | Phyto•Bears®, EM•Pact®,           |
|                                  | GlycoLEAN®, Plus®, Ambrostart®,   |
|                                  | Sport®, Emprizone®                |
+----------------------------------+-----------------------------------+
| [Mary Kay,                       | Daily Benefits for Women®, Daily  |
| Inc.](http://www.marykay.com/)   | Benefits for Men®                 |
+----------------------------------+-----------------------------------+
| ### [*Natur                      | ### Pathway to                    |
| al Alternatives International In | Healing®, Jennifer O'Neill Essent |
| c.*](http://www.nai-online.com/) | ials®, Private Label Manufacturer |
+----------------------------------+-----------------------------------+
| [NBTY,                           | Nature\'s Bounty®, Vitamin        |
| Inc.](http://www.corpor          | World®, Puritan\'s Pride®,        |
| ate-ir.net/ireye/ir_site.zhtml?t | Holland & Barrett®, Nutrition     |
| icker=NBTY&script=2100&layout=8) | Headquarters®, American Health®   |
|                                  | and Nutrition Warehouse®, Private |
|                                  | Label Manufacturer                |
+----------------------------------+-----------------------------------+
| [Nu Skin International           | LifePAK®, Phamanex Solutions®,    |
| Inc                              | Pharmanex Bodydesign®             |
| .](http://www.nuskinenterprises. |                                   |
| com/corp/index.shtml)/[Pharmanex |                                   |
| LLC](http://www.pharmanex.com/)  |                                   |
+----------------------------------+-----------------------------------+

+----------------------------------+-----------------------------------+
| ######## Ma                      |                                   |
| nufacturers of Finished Products |                                   |
+----------------------------------+-----------------------------------+
| # Member Company                 | # Products                        |
+----------------------------------+-----------------------------------+
| [Nutraceutical                   | Solaray®, KAL®, NaturalMax®,      |
| Corporation                      | VegLife®, Premier One®, Sunny     |
| ](http://www.nutraceutical.com/) | Green®, Natural Sport®, ActiPet®, |
|                                  | Action Labs®, Miztique®, Ultimate |
|                                  | Nutrition® and Thompson®, Private |
|                                  | Label Manufacturer                |
+----------------------------------+-----------------------------------+
| [Nutramax Laboratories,          | Senior Moment®, Cosamin® DS       |
| Inc                              |                                   |
| .](http://www.nutramaxlabs.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Perrigo                         | Private Label Manufacturer and    |
| Company](http://                 | Branded Contract Manufacturer     |
| www.perrigo.com/index_flash.htm) |                                   |
+----------------------------------+-----------------------------------+
| [Pharmaton Natural Health        | Ginsana®, Ginkoba®, Flexium®,     |
| Products](http://ww              | Kyolic®, Venastat®, Supplifem®,   |
| w.pharmaton.com/us/homepage.jsp) | Prostatonin®                      |
+----------------------------------+-----------------------------------+
| [Pharmavite                      | Nature Made®, Nature's Resource®, |
| LLC](http://www.pharmavite.com/) | Private Label Manufacturer, Olay™ |
|                                  | Vitamins                          |
+----------------------------------+-----------------------------------+
| [Proper Nutrition,               | SeaCure®, SeaVive®                |
| Inc.](                           |                                   |
| http://www.propernutrition.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Pulse                           | Pulse® Water + Nutrients          |
| Nutrition](http://www.pul        | (Vitamins and Minerals)           |
| senutrition.com/html/index.html) |                                   |
+----------------------------------+-----------------------------------+
| [Rainbow Light Nutritional       | Active Health®, Complete          |
| System                           | Nutritional System®, Complete     |
| s](http://www.rainbowlight.com/) | Prenatal System®, Nutristars®,    |
|                                  | Performance Energy®, Women's      |
|                                  | Answer® and other Single          |
|                                  | Nutrient, Herbal, and Specialty   |
|                                  | Supplements                       |
+----------------------------------+-----------------------------------+
| [Rexall Sundown,                 | Sundown®, Osteo Bi-Flex®,         |
| Inc.                             | Pokemon®, Private Label           |
| ](http://www.rexallsundown.com/) | Manufacturer                      |
|                                  |                                   |
| (now part of NBTY, Inc.)         |                                   |
+----------------------------------+-----------------------------------+
| [Ross                            | Glucerna®, Ensure®, Infant        |
| Products](http://www.ross.com/)  | Formula                           |
+----------------------------------+-----------------------------------+
| [Shaklee                         | CorEnergy®, Mood-Lift®,           |
| Corpo                            | Vita-Lea®, CoQHeart®, Immunity    |
| ration](http://www.shaklee.com/) | Formula I®, Herb-Lax®,            |
|                                  | Optiflora®, EZ-Gest®, Shaklee     |
|                                  | Fitness®, Performance®,           |
|                                  | Physique®, Liver DTX®, Fiber      |
|                                  | Plan®                             |
+----------------------------------+-----------------------------------+
| [Sigma Tau Health                | ## Pro                            |
| Sciences](http:/                 | Xeed®, Megasol®, Megasol Q10®, Ph |
| /www.sigmatau-hs.it/default.htm) | ototrop®, Avant®, Biorecord Plus® |
+----------------------------------+-----------------------------------+
| [Tom's of                        | Botanicals                        |
| Mai                              |                                   |
| ne](http://www.tomsofmaine.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Vitamin Shoppe Industries,      | Vitamins and Minerals, Specialty  |
| Inc.                             | Supplements, and Botanicals       |
| ](http://www.vitaminshoppe.com/) | distributed under the Vitamin     |
|                                  | Shoppe® name                      |
+----------------------------------+-----------------------------------+
| [VitaTech International,         | Private Label Manufacturer        |
| Inc.](http://www.vitatech.com/)  |                                   |
+----------------------------------+-----------------------------------+
| [Warner Lambert Consumer Group   | Finished Product Manufacturer     |
| of                               |                                   |
| Pfizer](                         |                                   |
| http://www.pfizer.com/main.html) |                                   |
+----------------------------------+-----------------------------------+
| [Weider Nutrition International, | Schiff®, Schiff® Move Free®,      |
| Inc.](http                       | Tiger's Milk®, Weider®, Fi Bar®   |
| ://www.weidernutrition.biz/weide |                                   |
| r_interior.asp?strLink=investor) |                                   |
+----------------------------------+-----------------------------------+
| [Wyeth](http://www.wyeth.com/)   | Centrum®, Centrum Silver®,        |
|                                  | Centrum Performance®, Centrum     |
|                                  | Kids®, Caltrate®                  |
+----------------------------------+-----------------------------------+

+----------------------------------+-----------------------------------+
| ####### **Suppliers**            |                                   |
+----------------------------------+-----------------------------------+
| # Member Company                 | # Products/Ingredients/Services   |
+----------------------------------+-----------------------------------+
| [Access Business Group - Trout   | Grower and Processor of Botanical |
| Lake                             | Ingredients, Ocean Essentials®    |
| Farms](http://www.acce           |                                   |
| ssbusinessgroup.com/default.asp) |                                   |
+----------------------------------+-----------------------------------+
| [Albion Laboratories,            | Bulk Minerals                     |
| Inc.](http://www.albion-an.com/) |                                   |
+----------------------------------+-----------------------------------+
| [American Laboratories,          | Processor and Supplier of         |
| Inc.](http:                      | Enzymes, Peptones, Liver Products |
| //www.americanlaboratories.com/) | and Glandulars                    |
+----------------------------------+-----------------------------------+
| [Archer Daniels Midland          | Vitamin E, Soy Isoflavones,       |
| Co                               | Lecithin                          |
| mpany](http://www.admworld.com/) |                                   |
+----------------------------------+-----------------------------------+
| [B&D Nutritional Ingredients,    | ##                                |
| Inc.](http://www.bndni.com/)     |  Supplier of Vitamin E, Lecithin, |
|                                  |  Lutein, Phytosterols, Grape Seed |
+----------------------------------+-----------------------------------+
| [BASF                            | Vitamins A, C, D & E, B Vitamins, |
| Co                               | Carotenoids, Excipients,          |
| rporation](http://www.basf.com/) | Clarifying Agents, Aroma          |
|                                  | Chemicals                         |
+----------------------------------+-----------------------------------+
| [Biotron Laboratories,           | Supplier of Various Mineral Amino |
| In                               | Acid Chelates                     |
| c.](http://www.biotronlabs.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Cap                             | Encapsulated Products and         |
| sugel](http://www.capsugel.com/) | Capsules                          |
+----------------------------------+-----------------------------------+
| [Cargill Health & Food           | Soy Isoflavones, Chondroitin,     |
| Techno                           | Vitamin E                         |
| logies](http://www.cargill.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Cognis Nutrition &              | Natural Vitamin E, Tonalin® CLA,  |
| Health](ht                       | Vegapure®, Sterols/Sterol Esters, |
| tp://www.cognis.com/cognis.html) | Lutein Esters, Natural Mixed      |
|                                  | Carotenoids, ALA, Botanicals,     |
|                                  | Emulsifiers, Food Technology      |
|                                  | Ingredients                       |
+----------------------------------+-----------------------------------+
| [Col                             | Excipients, Colors, Coating       |
| orcon](http://www.colorcon.com/) | Systems, Printing Inks            |
+----------------------------------+-----------------------------------+
| [Daiichi Fine Chemicals,         | B Vitamins, Vitamin D,            |
| Inc.](http://www                 | Carotenoids                       |
| .daiichi-fcj.co.jp/en/home.html) |                                   |
+----------------------------------+-----------------------------------+
| [E.T. Horn                       | Bulk Ingredients Including:       |
| Company](http://www.ethorn.com/) | Calcium Carbonate, Glucosamine,   |
|                                  | Cellulose                         |
+----------------------------------+-----------------------------------+
| [Generichem                      | Bulk Supplier of Minerals         |
| Corporat                         |                                   |
| ion](http://www.generichem.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Indena USA,                     | Botanicals Supplier               |
| Inc.](http://www.indena.com/)    |                                   |
+----------------------------------+-----------------------------------+
| [Kaneka America                  | ## Supplier of Co-Enzyme Q10      |
| Corporation](ht                  |                                   |
| tp://www.kaneka.com/kacfine.htm) |                                   |
+----------------------------------+-----------------------------------+
| [Kemin Foods,                    | Lutein - FloraGLO®, Antioxidants  |
| L.C.](http://www.kemin.com/)     |                                   |
+----------------------------------+-----------------------------------+
| [Linnea,                         | Botanicals Supplier               |
| Inc.](http://www                 |                                   |
| .linnea-worldwide.com/home1.asp) |                                   |
+----------------------------------+-----------------------------------+
| ### [*Loders-Crok                | ### Suppl                         |
| laan*](http://www.croklaan.com/) | ier of Oils Including: Clarinol®, |
|                                  |  Marinol®, Membranol®, Safflorin® |
+----------------------------------+-----------------------------------+
| [Lonza,                          | Supplier of L-Carnitine and B     |
| Inc.](http://w                   | Vitamins                          |
| ww.lonzagroup.com/group/en.html) |                                   |
+----------------------------------+-----------------------------------+
| Mingtai Chemical, LLC            | ## Micro                          |
|                                  | crystalline Cellulose, Comprecal® |
+----------------------------------+-----------------------------------+
| [Nashai Biotech                  | Supplier of Ingredients Including |
| LLC](http://www.nashai.com/)     | TeaFlavin®                        |
+----------------------------------+-----------------------------------+
| [Nutrinova](http://www.nu        | DHActive®, Fiber - Caromax®,      |
| trinova.com/easy2web/internet.ns | Nutrinova® Sorbates               |
| f/directframe/home?OpenDocument) |                                   |
+----------------------------------+-----------------------------------+
| [Nutrition 21,                   | Chromax® Chromium Picolinate,     |
| In                               | Zinmax® Zinc Picolinate,          |
| c.](http://www.nutrition21.com/) | Selenomax® High Selenium Yeast,   |
|                                  | Selenopure® l-selenomethionine,   |
|                                  |                                   |
|                                  | Zenergen™ Chromium Picolinate     |
|                                  | plus CLA                          |
+----------------------------------+-----------------------------------+
| [Ocean Nutrition Canada          | Omega-3 Fatty Acids               |
| Ltd.](                           |                                   |
| http://www.ocean-nutrition.com/) |                                   |
+----------------------------------+-----------------------------------+
| [Omya,                           | Supplier of Calcium Carbonate     |
| Inc.](http://www.omya-na.com/)   |                                   |
+----------------------------------+-----------------------------------+
| [Polyphenolics                   | MegaNatural® Gold Grape Seed      |
| ](http://www.polyphenolics.com/) | Extract, MegaNatural® Grape Skin  |
|                                  | Extracts, MegaNatural® Rubired    |
|                                  | Grape Juice Extract, MegaNatural® |
|                                  | Red Wine Extract                  |
+----------------------------------+-----------------------------------+
| ###### Suppliers                 |                                   |
+----------------------------------+-----------------------------------+
| # Member Company                 | # Products/Ingredients/Services   |
+----------------------------------+-----------------------------------+
| [Pronova Biocare,                | Omega-3 Fatty Acids - EPAX®,      |
| a.s.](http://w                   | Triomega®, Pikasol®, Omacor®      |
| ww.pronovabiocare.com/index.php) |                                   |
+----------------------------------+-----------------------------------+
| [Rhodia,                         | Calcium Phosphate, Probiotics     |
| Inc.](http://w                   |                                   |
| ww.rhodia.com/us/home_tunel.asp) |                                   |
+----------------------------------+-----------------------------------+
| [Roche Vitamins,                 | Vitamins A, C, D, & E, B          |
| Inc.]                            | Vitamins, Carotenoids, Omega-3    |
| (http://www.roche.com/home.html) | Fatty Acids                       |
+----------------------------------+-----------------------------------+
| [Seven Seas                      | Fish Oils, Multivitamins, Evening |
| Limited                          | Primrose Oil, Herbals,            |
| ](http://www.seven-seas.ltd.uk/) | ActionPlan50+®                    |
+----------------------------------+-----------------------------------+