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**Bio-Rad** Diagnostics Group

> **Laboratories** 9500 Jeronimo Road
>
> Irvine, California 92618-2017

Telephone: (949) 598-1200

December 29, 2003

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Rm. 1061

Rockville, MD 20852

RE: Docket \# 2003D-0383

Dear Sir or Madam:

On behalf of Bio-Rad Laboratories, I am submitting a response to the
Food and Drug Administration regarding Docket number 2003D-0383, Use of
Symbols on Labels and in Labeling of In Vitro Diagnostic Devices
Intended for Professional Use.

Bio-Rad Laboratories applauds the Food and Drug Administration's
decision to publish this draft guidance document, as it is a reasonable
step to harmonize with some of the international labeling requirements,
which American manufacturers have been required to comply with for many
years. Bio-Rad Laboratories has a number of comments advocating the
recognition of additional symbols. These comments have been provided on
the following pages.

Should you have any comments related to this response, please contact me
directly or one of my associates at the correspondence information
provided below.

Thank you.

With best regards,

+-----------------------+----------------------+----------------------+
| Donna Chapman         | Elizabeth Platt      | Yvette Lloyd         |
|                       |                      |                      |
| RA/QA Manager         | RA Manager           | Senior Regulatory    |
|                       |                      |                      |
| Bio-Rad Laboratories  | Bio-Rad Laboratories | Affairs Specialist   |
|                       |                      |                      |
| Irvine, CA 92618      | Irvine, CA 92618     | Bio-Rad Laboratories |
|                       |                      |                      |
| Phone: 949-598-1280   | Phone: 949-598-1285  | Irvine, CA 92618     |
|                       |                      |                      |
| Fax: 949/598-1555     | Fax: 949/598-1555    | Phone: 949-598-1465  |
|                       |                      |                      |
| e-mail:               | e-mail:              | Fax: 949/598-1555    |
|                       |                      |                      |
| donn                  | elizabeth_platt      | e-mail:              |
| a_chapman@bio-rad.com | \@bio-rad.com        |                      |
|                       |                      | Yvet                 |
|                       |                      | te_lloyd@bio-rad.com |
+-----------------------+----------------------+----------------------+

1.  **Bio-Rad Laboratories would like the Food and Drug Administration
    to recognize additional symbols.**

> Bio-Rad Laboratories recommends that the Food and Drug Administration
> ("FDA") adopt additional symbols without the use of English subtext to
> render the product compliant with the labeling regulations, such as 21
> C.F.R. § 809.10. Bio-Rad Laboratories believes that the FDA has taken
> substantial steps in recognizing the 25 symbols identified in the
> document, however, Bio-Rad Laboratories recommends that the FDA could
> adopt the use of additional symbols than those identified in the
> document.
>
> There are additional symbols that *in-vitro* diagnostic manufacturers
> may use on labeling to convey the information. For example, many
> manufacturers may utilize the symbols in ISO 7000, "GRAPHICAL SYMBOLS
> FOR USE ON EQUIPMENT," on reagent analyzers or the accompanying
> equipment for use with *in-vitro* diagnostic products. These products
> often have extensive labeling in the form of product manuals, and the
> use of the symbols in ISO 7000 may enhance the readability of the
> document because the symbols may be easier for the end-user to
> understand than the myriad of text required.
>
> Another example is found in the Directive 98/79/EC of the European
> Parliament and of the Council of 27 October 1998 on *in-vitro*
> diagnostic medical devices, which requires the use of symbols to
> convey information about hazardous materials in the products.
>
> Manufacturers are required to convey hazard information in the forms
> of symbols as necessary. The FDA labeling regulations accord the
> requirement to provide hazard information to the end-user. See, 21.
> C.F.R. § 809.10(a)(4). Therefore, Bio-Rad Laboratories recommends to
> the FDA, that additional recognized symbols should be considered for
> use in the final guidance document.
>
> In addition, Bio-Rad Laboratories recommends that the FDA address
> continuing adoption of symbols by the international community.
> Standards, whether harmonized or from an international standards
> organization, are likely to change over time, as the international
> communities adopt additional symbols for use on medical device
> labeling. As the draft guidance is currently written, the FDA
> recognizes only 25 symbols from the current versions of ISO 15523,
> "MEDICAL DEVICES -- SYMBOLS TO BE USED WITH MEDICAL DEVICE LABELS,
> LABELING AND INFORMATION TO BE SUPPLIED" and EN 980, "GRAPHICAL
> SYMBOLS FOR USE IN THE LABELING OF MEDICAL DEVICES." The international
> communities may adopt additional symbols resulting in a change to
> these documents, or in the creation of a wholly new standard on
> symbols. The current draft guidance document has no means to address
> the potential dynamic nature of the standards. Therefore, Bio-Rad
> Laboratories recommends that the FDA address in the final guidance
> document the use of newly recognized symbols.

2.  **Bio-Rad Laboratories would like the Food and Drug Administration
    to address the use of non-harmonized symbols.**

> Bio-Rad Laboratories recommends that the FDA address the use of
> symbols that are not considered "harmonized" or have not yet been
> adopted by international standards bodies. Manufacturers have switched
> to symbols in order to comply with the requirements in the Directive
> 98/79/EC of the European Parliament and of the Council of 27 October
> 1998 on *in vitro* diagnostic medical devices, Official Journal L 331,
> 07/12/1998 P. 0001-0037 ("*In Vitro* Diagnostic Directive", or
> "IVDD"). The labeling requirements provide that, "the information to
> be supplied should take the form of symbols." *Id* at § 8.2. In
> addition, the requirements suggest that, "any symbol and
> identification color used must conform to the harmonized standards."

This latter requirement is interpreted to mean that when a harmonized or
recognized symbol exists, the manufacturer must use the symbol that has
been recognized and cannot create a new symbol in lieu of the accepted
symbol. Nonetheless, there are situations where a manufacturer may be
forced to create a new symbol because there exists no symbol that has
been recognized that conveys the information. The European regulations
do allow this practice by stating, "in areas for which no standards
exist, the symbols and color used must be described in the documentation
supplied with the device." Bio-Rad Laboratories believes that because
the picture itself is self-explanatory and the symbol would be explained
in the glossary, no English subtext should be required in order to
render the labeling compliant as interpreted by the Act. In duly noted
cases, English subtext may be required when a symbol cannot be readily
known from the picture itself.

Where a manufacturer uses a novel symbol, the manufacturer should
conduct a reasonable search of the labeling standards to ensure that the
symbol is novel. In addition, the manufacturer should consider
researching labeling of different types of industries to ensure that the
symbol has not been used in an alternative format to convey a different
meaning. Additional guidance for the development of "custom" or
non-harmonized" symbols may be found in the European Diagnostic
Manufacturers Association ("EDMA") Guidance Document, EDMA Symbols for
IVD reagents/components," Revision 8 February 2002. If the FDA does not
have a copy of the document, Bio-Rad Laboratories can provide as
necessary. Bio-Rad Laboratories recommends that the FDA address the use
of non-harmonized symbols without English subtext in the final guidance
document.

Bio-Rad Laboratories recommends that the FDA address the use of
non-harmonized symbols accompanied with English subtext as an
alternative proposition when there are "custom" or "non-harmonized
symbols" that are not self evident from the pictorial form. The FDA
general labeling regulations provide that, "if the label contains any
representation in a foreign language, all words, statements, and other
information required by or under authority of the act to appear on the
label shall appear thereon in the foreign language." 21 C.F.R. §
801.15(c)(2). This requirement can be interpreted to apply to a package
label. The regulations also allow for other labeling because the
regulations indicate, "if the labeling contains any representation in a
foreign language, all words, statements, and other information required
by or under authority of the act to appear on the label or labeling
shall appear on the labeling in the foreign language." *Id,* at
subsection (3).

These regulations may apply to the use of "custom" or "non-harmonized"
symbols because these labeling requirements imply that a device would be
misbranded if, on a particular label, it bears a non-harmonized symbol
with English subtext and non subtext for the other languages, since the
other languages are represented elsewhere in the labeling. Bio-Rad
Laboratories makes this assessment because the FDA states in the draft
guidance document that, "FDA concludes that the symbols from
international consensus standard recognized in this guidance document
can be understood by relevant users in the United States and thus
satisfy the underlying requirements of Section 502(c), the Agency does
not intend to interpret their use to violate 21 C.F.R. § 801.15 (c)."
Draft guidance, Footnote 1. This statement by the FDA suggests
therefore, that FDA will accept any of the harmonized symbols recognized
by the document as equivalent to representation in English and that
English subtext is not required. However, this implies that English
subtext would be required for "non-harmonized" symbols are harmonized
symbols not recognized by the draft guidance.

Bio-Rad Laboratories advocates the use of no English subtext where the
meaning of the symbol is self-evident. For a "non-harmonized" or
"custom" symbol, the symbol itself would be the pictorial representation
of the intended meaning of the text, and it would be explained in the
package insert. Therefore, if the FDA were to recommend the use of
English subtext for symbols that are not self-evident from the pictorial
representation, Bio-Rad Laboratories recommends that the final guidance
could resolve this issue by stating that the FDA considers the
non-harmonized symbol (with English subtext) to be representative of the
other languages, as long as the symbol is included in an accompanying
glossary containing all represented languages.