From: sharon.olmstead@pharma.novartis.com

Sent: Friday, June 22, 2001 3:02 PM

To: fdadockets@oc.fda.gov

Subject: Electronic Comments to 00N-1269

Please find for submission to the FDA docket the attached comments from

Novartis Pharmaceuticals Corp. for docket \# 00N-1269, \"Requirements on

Content and Format of Labeling for Human Prescription Drugs and
Biologics;

Requirement s for Prescription Drug Product Labels; Proposed Rule\" due
June

22, 2001.

If you have any questions or technical problems with this electronic

submission, please contact me at 301-468-5607.

Sharon Olmstead

Executive Director

Drug Regulatory Affairs

(See attached file: labeling comments final.doc)

+----------------------------+--------------+-------------------------+
|                            | **Mathias    | **Novartis              |
|                            | Hukkelhoven, | Pharmaceuticals         |
|                            | Ph.D.**\     | Corporation**\          |
|                            | Vice         | Drug Regulatory         |
|                            | President\   | Affairs\                |
|                            | US Head      | 59 Route 10\            |
|                            |              | East Hanover, NJ        |
|                            |              | 07936-1080\             |
|                            |              | \                       |
|                            |              | Tel 973 781 6035        |
|                            |              |                         |
|                            |              | Fax 973 781 3966\       |
|                            |              | email:                  |
|                            |              | mathias.hukkelho        |
|                            |              | ven@pharma.novartis.com |
+----------------------------+--------------+-------------------------+

Dockets Management Branch (HFA-305)

Food and Drug Administrative

5630 Fishers Lane, Room 1061

Rockville, MD 20852

June 22, 2001

### FDA Docket No. 00N-1269

**Requirements on Content and Format of Labeling for Human Prescription
Drugs and Biologics; Requirements for Prescription Drug Product Labels;
Proposed Rule**

Dear Sir/Madam:

As a leader in the discovery, development, manufacture and marketing of
prescription medicines, Novartis Pharmaceuticals Corporation is
committed to improving health and well-being through innovative products
and services. We would like to take this opportunity to comment on FDA's
proposal, "Requirements on Content and Format of Labeling for Human
Prescription Drugs and Biologics; Requirements for Prescription Drug
Product Labels." Novartis applauds FDA's effort to improve prescription
drug labeling and supports implementation of the majority of the
features of the reformatted COMPREHENSIVE PRESCRIBING INFORMATION
section as described in the proposal. We believe that, over the past 20
years, the impact of critical data about dosing, adverse effects, and
drug interactions has been diluted by the extensive verbiage surrounding
it. We believe the proposed reorganization and bolding of section
headings and subheadings will accomplish the agency's goals of improving
readability and enhancing the safe and effective use of prescription
drug products. However, Novartis does not support the inclusion of a
HIGHLIGHTS section or an INDEX prior to the comprehensive labeling. We
have outlined our comments on the current proposal as follows:

### Highlights of Prescribing Information \[proposed § 201.56(d) & 201.57(a)\]

-   **Appropriateness of Including a "Highlights" Section**

> Novartis does not support the addition of a "highlights" section to
> prescription drug labeling. The sequestration of selected data under
> that heading will not increase the readability or comprehensibility of
> the prescribing information, and is likely to create the
> misapprehension that the information presented in such a section is
> agreed, by both the manufacturer and the FDA to be the **most
> important** to the prescriber and consumer. In fact, significant
> features of the safety profile of the product will need to remain only
> in the "comprehensive" section, where they may never be viewed by
> either party.
>
> To designate some data as "highlights" perforce decreases the focus on
> non-highlighted issues, and could, by omission, unintentionally
> increase the risk to the very patients FDA seeks to protect. Moreover,
> the stratification of safety data may discourage healthcare providers
> and interested consumers from viewing the comprehensive information
> section, thereby increasing the potential for misinterpretation of the
> data -- **all** safety data included in the package insert are
> important, but will no longer appear so when they are divided between
> two sections of the document.
>
> More than ever before, patients are participating in their own
> healthcare. If the prescribing information is to be among the
> foundation blocks of their understanding of the therapies they
> receive, it must present information that is both balanced and as
> complete as possible. The abbreviation of information, could mislead
> patients regarding the importance of safety and adverse reaction
> "signals" they experience. As a result, these patients could
> potentially develop serious complications which could have been
> preventable with earlier recognition of their relation to drug
> therapy.
>
> Finally, FDA's proposal to summarize the most "clinically significant"
> events under the combined "Warnings/Precautions" heading is likely to
> lead to inconsistency across products and between reviewing divisions,
> based on the absence of a single standard for "significance" as well
> as the differences in judgement exercised by manufacturers and FDA
> reviewers.
>
> In summary, the information contained within the
> "Warnings/Precautions" section serves as a crucial component in a
> healthcare provider's assessment when prescribing medications for
> his/her patients and should not be selectively or arbitrarily
> abbreviated in a separate "highlights" section. Novartis sees such a
> section as inconsistent with the agency's efforts to improve the value
> of the package insert to healthcare practitioners and consumers and,
> therefore, does not support the addition of "highlights" to the
> prescribing information.

-   **Proposal to limit the highlight section to one-half page**

> As detailed above, Novartis does not support the inclusion of a
> "highlights" section. However, should FDA require it, the space
> allotted to such a section cannot, to adequately support good medical
> practice, be limited. The decision of what must be listed there should
> take into account the extent of critical information contained within
> the verbatim text of the boxed warnings, indication and usage
> information, contraindications, and adverse reaction information.

-   **Liability associated with the highlight section**

Novartis believes the disclaimer at the end of the "highlights" section
to be insufficient to protect against product liability claims if a
patient experiences an adverse event described in the comprehensive
labeling but not the "highlights" section. The omission of such
information is almost certain to be used in a plaintiff's case as a
contributing factor to the harm experienced by the patient. Therefore,
we believe the net effect of the highlight section and its disclaimer
will increase the exposure of pharmaceutical companies to product
liability suits. FDA's suggestion to the contrary is unfounded. The
outcomes of numerous class actions in which plaintiffs have been awarded
enormous, bankrupting sums in compensation for the occurrence of
"labeled" adverse events serve to undercut FDA's view. Any limitation on
the prosecution of, or awards given in, drug product liability cases
based on labeled safety information would require a statutory solution
unlikely to be obtainable in a time frame FDA would find acceptable.

-   **Highlights "Reminder" Statement \[proposed § 201.57(a)(15)\]**

Although Novartis does not support the use of a highlight section, if
such a section is included in the final rule, Novartis proposes that the
"reminder" statement be moved to the beginning of the highlight section.
Such a revision in formatting will alert the reader to the abbreviated
nature of the information contained in the highlights section.
Additionally, the currently proposed statement should be revised and
bolded or underlined to draw the reader's attention. Novartis also
proposes the following alternatives for the highlights reminder
statement: "These highlights do not describe all of the potential safety
hazards that a practitioner might convey to the patient before obtaining
an informed consent to therapy. For complete safety information, the
label must be reviewed in its entirety" or "This highlights section may
not contain the most important information for an individual patient.
The judgement of what data may be of particular importance to a specific
patient rests with the prescribing physician."

-   **Boxed Warning \[proposed** **§ 201.57(a)(4)\]**

```{=html}
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-   **Limiting Boxed Warnings to Text of 20 Lines**

> FDA is proposing in the highlight section to limit the boxed warning
> to 20 lines of text. FDA should consider that 20 lines of a two-inch
> column width are very different from 20 lines of a three-inch column
> width or wider. The current proposal could result in some products
> with boxed warnings having less information than others within the
> same class. Novartis does not support the use of a highlight section
> and therefore, does not support the use of an abbreviated boxed
> warning. If the highlight section is adopted, Novartis recommends the
> inclusion of the full bolded text for boxed warnings in the highlight
> section. Similar to the concerns raised by the creation of an
> abbreviated list of adverse events in the combined
> Warnings/Precautions section, limiting the text in the boxed warning
> could lead to further inconsistencies between products.

-   **Boxed Warning Icon (!)**

The current "black" boxed warning is considered a universally recognized
component of the US product labeling. Additional icons seem unnecessary
and provide little added value to the comprehension of the product
labeling. Additionally, the inclusion of symbols in the product labeling
can create problems with the software used to generate text, print
labeling and prepare electronic labeling.

-   **Inverted Black Triangle Symbol \[proposed § 201(a)(2)\]**

> Novartis does not support the use of a symbol or icon to identify
> products that have been commercially available in the US for 3 years
> or less. FDA would be required to conduct an extensive educational
> campaign to introduce the meaning of such a symbol with no assurance
> that the use of such an icon would provide the intended effect. The
> use of icons historically has not been a successful method of
> conveying important public health information and in some cases can
> produce unintended effects.

-   **Recent Labeling Changes \[proposed § 201.57(a)(5)\]**

> Novartis supports the creation of a "Recent Labeling Changes" section
> which identifies (and specifies the effective date for) information
> added to the insert and displays that information for **at least** one
> year after the date of the addition. Novartis supports FDA's proposal
> that such information be retained in that section until the next
> printing that occurs after 12 months have elapsed. This would prevent
> an unwarranted disposal of appropriate labeling and an unnecessary
> increase in cost of goods.

-   **Indications and Usage \[proposed § 201.57(a)(6)\]**

> Novartis does not support the use of a summary "indications and usage"
> section in the highlight section. Certain products currently on the
> market include limitations on the patient population in the
> indications and usage section. Under the current proposal, such
> limitation in product use for certain patients may not be included in
> the summary and could pose safety risks if prescribed inappropriately
> based on the summary information. If the highlight section as proposed
> by FDA remains in the final rule, Novartis proposes the indications
> and usage section contain the language found in the comprehensive
> labeling verbatim.

-   **Contacts for ADR Reporting \[proposed § 201.57(a)(11)\]**

> Novartis agrees with FDA's proposal to include contact information.

### Comprehensive Prescribing Information: Index \[proposed § 201.57(b)\]

Novartis believes the reformatting of the comprehensive labeling will
achieve the goals set by FDA to improve the readability of packaged
inserts, allowing healthcare professionals and patients to find
"specific information and discern the most critical information in the
product labeling." Based on the current proposal, the index coupled with
the increased font size will add unnecessary length and size to the
package insert. Therefore, Novartis proposes that the index and number
placement be reserved for electronic labeling only. The index will
supplement the reformatted comprehensive information when electronic
labeling becomes a common source of product information for healthcare
professionals.

**Comprehensive Prescribing Information \[proposed § 201.56(d) &
201.57(c)\]**

> Novartis supports the proposal to reformat the comprehensive
> prescribing information. The reorganization of information will
> facilitate healthcare providers in safely and effectively prescribing
> medication to their patients. Again, Novartis believes it is change to
> the prescription drug labeling and not the proposed "Highlights"
> section that will produce the effect FDA hopes to achieve through
> implementation of this proposal.

-   **Boxed Warnings \[proposed §§ 201.57(c)(1)\]**

> As mentioned previously, icons (!) seem unnecessary and provide little
> added value to the comprehension of the product labeling.

-   **Implied/Suggested Indications, Uses, or Dosing \[proposed § §
    201.57(c)(2)(ii) & (iii), (3), (13) & (15)\]**

> FDA has proposed the removal of clinical data describing indications,
> usage, and dosing if those data are not authorized in the "Indications
> and Usage" and "Dosage and Administration" sections. Novartis believes
> that such information, which is obtained using commonly accepted
> scientific methods via protocols approved by the agency, provides
> healthcare practitioners with a more complete safety and efficacy
> profile of the product and should not be summarily excluded. Such
> information has always been, and should continue to be, reviewed and
> approved by FDA prior to inclusion in the labeling. FDA has, however,
> proposed the inclusion of a warning in the "Warnings/Precautions"
> section for those off-label uses not included among approved
> indications but which may present a clinically significant risk or
> hazard. The same purpose is served by both placement of this warning
> and the continued inclusion of clinical data obtained from
> investigation of unapproved uses and dosing regimens or levels \-- to
> provide the healthcare practitioners with a complete understanding of
> a product's safety and efficacy profile.

-   **Adverse Reactions \[proposed § 201.57(c)(9)\]**

> The FDA proposal has introduced several new terms without adequate
> definitions such as "noxious", "injurious to health", as well as the
> new standard of "reasonable causation." It is difficult to comment on
> this section of the proposal without further clarification. However,
> the usual language regarding ADR's is that they are anecdotal reports
> that at most, represent a possible signal which must be closely
> examined. They are not evidence of causation and it would not be in
> the patient's or prescriber's best interests to assume automatically
> that an ADR is evidence of causation. Doing so would impede the
> ability of the prescriber to conduct an appropriate risk/benefit
> analysis of the drug, and would otherwise hinder the medical
> practitioner's ability to differentiate between events which are
> likely associated with the drug and those which are not.

### Format Requirements \[proposed § 201.57(d)\]

> Novartis supports FDA\'s proposal to require bolded headings and
> subheading for visual prominence. The bolded text will facilitate the
> navigation through the newly formatted comprehensive labeling as
> proposed under § 201.57(c). As previously stated, Novartis does not
> support the use of a highlight section but in the event this section
> is adopted in the final rule, Novartis would support the use of bolded
> headings and subheading.

-   **Font Size \[proposed § 201.57(d)(6)\]**

> FDA's proposal to change the size of the type to 8 or 10 point is
> projected to significantly increase the relative size of each package
> insert. While increasing the size of the package insert may seem like
> a minor issue, the projected increase will have a number of very
> significant impacts. For example, the proposed changes in font size
> coupled with the formatting changes to include a highlight and index
> section will [at]{.underline} [least]{.underline} double the size of
> our current package inserts thereby using more paper, more ink, more
> solvents and more energy to print, fold and attach each package insert
> to each trade package. Manufacturers involved in the printing and
> folding of the revised package insert would need to retool equipment
> leading to additional expenditures. Since manufacturer trade packages
> go through wholesalers, distributors, and/or major pharmacy chains to
> pharmacies, hospitals, and other healthcare institutions
> ([not]{.underline} to prescribing physicians), the majority of package
> inserts attached to the trade packages are immediately discarded at
> the various dispensing institutions (each only needs to keep 1 or 2 on
> hand for reference). As a result of the projected increase in size,
> there will be a proportional increase in waste. Across the
> pharmaceutical industry, even with recycling, this proposal could
> result in hundreds of tons of additional waste. The increased package
> insert size will require a different technique for attaching the
> package insert to each trade package, as the newly formatted labeling
> will be too large to fold and adhere to each bottle. [If]{.underline}
> the package insert could be folded down to the appropriate size to fit
> on the bottle, the glue would have to be so strong to hold the package
> insert on the trade package that it would likely tear when removing
> it, possibly negating the desired availability of the information. To
> avoid such problems manufacturers would need to invest in folding box
> cartons and retool the equipment to handle larger box cartons and the
> insertion of the labeling. The use of a folding box carton to contain
> the bottle with the package insert would add a cost increase of at
> least \$0.05/package and also increase the amount of paperboard (i.e.,
> wood product) consumed and ultimately wasted. This will also slow down
> the packaging operation. A large pharmaceutical company can produce
> over 45 million trade packages each year (\$0.05 x 45 million = \> \$2
> million dollars annual cost). The addition of a folding box carton
> would likely contain text that would have to be reviewed and approved
> by FDA and maintained by the sponsor resulting in additional
> regulatory burden. Finally, although increasing the size of the
> package insert would increase the overall dimensions of each package
> only slightly, when we combine packages together to be put into
> corrugated shippers, manufacturers would not be able to include the
> normal count of 72 trade packages into each existing size shipper.
> This will necessitate either increasing the size of the corrugated
> shippers or using more shippers to transport the same amount of
> product, thereby, increasing the cost and also the amount of
> corrugated material (i.e., wood product) consumed and ultimately
> wasted. Over the course of each entire lot/batch size, increased
> overall package / shipper size (i.e., the cube volume) will also
> necessitate more wooden pallets to store and transport the same amount
> of product, more storage space needed, more transportation costs
> (i.e., fuel, emissions, etc.).

-   **Vertical Line Identifying New Labeling Information in the
    Comprehensive Information Section \[proposed § 201.57(d)(9)\]**

> Novartis agrees with FDA's intent to alert the healthcare professional
> to new prescribing information in the comprehensive labeling. However,
> Novartis does not agree with the proposed use of a vertical line to
> identify new information. The vertical line does not provide an
> intuitive link between the information bracketed and the relationship
> to the recent inclusion of new information. Additionally, the use of a
> vertical line, similar to the introduction of new icons, presents
> added technical formatting difficulties without a proven benefit to
> the prescribing healthcare professional.

**Prescription Drugs for Human Use \[proposed § 201.100\]**

> Novartis supports the proposed revisions to the product label and
> agrees the removal of certain information will improve the legibility
> and reduce the potential for medication errors, particularly for those
> products with small packaging configurations.

### Additional Comments

-   **Potential impact of the proposed rule on small entities**

> Novartis does not believe the economic impact has been accurately
> estimated, not just for small entities but for the entire industry
> involved in the creation and manufacturing of package inserts. As an
> example, FDA believes that changing the labels will not have much of
> an impact. We would strongly disagree, as any change to the labeling
> will have economic impact. According to the proposal the costs for
> changing the package insert would be about \$2,000 per product.
> Currently, for a package insert that is sent to an outside vendor to
> typeset, the cost is between \$1000 and \$2500. This does not include
> the cost of time for in-house staff to prepare the change to send to
> the artist and the proofreading or printing time. The costs for
> printing will depend on whether a sponsor uses one or two colors and
> the size of the final package insert. Finally, the cost of resulting
> from a font size change effecting the printing and folding of a larger
> package insert is addressed in our response to the proposed increase
> in font size under § 201.57(d)(6).

-   **Implementation timeframe**

> Novartis agrees with the proposed time schedule for those products
> marketed within 5 years following the implementation of a new labeling
> format. However, Novartis does not support the one-year implementation
> plan for \"older\" drugs. This proposal is overly burdensome and
> highly unlikely to provide the intended benefit, as newer products in
> the same therapeutic class supplant many older products. Additionally,
> the anticipated volume of submissions within one year of
> implementation would create a tremendous resource strain on FDA review
> staff leading to a new backlog in labeling supplements. The
> anticipated benefit suggested by FDA would be greatly diminished as
> the required labeling revisions would not reach the product labeling
> and hence the healthcare professional for several years or more.

In closing, Novartis appreciates the opportunity to comment on this
important new proposal and looks forward to working with FDA to achieve
labeling standards that will continue to ensure the safe and effective
use of all prescription drug products.

Sincerely,

/s/

Mathias Hukkelhoven, PhD

Vice President

US Head, Drug Regulatory Affairs

Novartis Pharmaceutical Corporation