Analysis of the Feasibility of Safety Labeling Changes Implementation Timeline Final

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Eastern Research Group, Inc. 110 Hartwell Ave. Lexington, MA 02421

Final Report: Analysis of the Feasibility of Safety Labeling Changes Implementation Timeline Final

Prepared for FDA under Contract No. HHSF223201110018B, Task 2

Prepared by Eastern Research Group, Inc. 110 Hartwell Ave Lexington, MA 02421

June 22, 2012

Table of Contents

1.0 EXECUTIVE SUMMARY and Introduction ...... 1

2.0 Typical SLC Timelines and Tasks ...... 2 2.1 SLC Priorities Set by Manufacturers ...... 3 2.2 Baseline Case Studies of Labeling Timelines ...... 4 2.2.1 High Priority SLC ...... 5 2.2.1.1 Receipt of FDA-Approved Language, Review, and Website Posting ...... 5 2.2.1.2 SPL Conversion and Artwork ...... 6 2.2.1.3 Label Printing ...... 6 2.2.1.4 Implementing Printed SLC in Production ...... 7 2.2.1.5 Packaged Product with SLC Enters Manufacturer's Inventory/Distribution Center ...... 8 2.2.2 New Drug Launch Timeline ...... 8 2.2.3 Low Priority SLCs ...... 9

3.0 Information Received from Other entities with roles in the SLC Process ...... 10 3.1 Information Received from Contract Printers ...... 10 3.2 Information Received from Contract Packagers ...... 12 3.3 Information Received from Wholesalers/Distributors/Retailers ...... 13 3.4 Information Received from Drug Information Vendors ...... 14

4.0 Specific Case Studies of SLCs ...... 16 4.1 Quinolones ...... 16 4.2 SLC Case Study 2 ...... 18

5.0 Exceptions to the Timelines and Tasks ...... 19 5.1 Unusual Printing Media ...... 19 5.2 PI Size Issues ...... 20 5.3 Medication Guide Additions ...... 21 5.4 Carton Size Changes ...... 21 5.5 Multiple Levels and Versions of Labeling ...... 22 5.6 Foreign Establishments ...... 22 5.7 Integration with Other Regulatory Requirements ...... 23 5.8 Generic vs. Branded Drugs ...... 23

6.0 Lessons Learned ...... 24

Appendix A: Summary of NODA Comments ...... 1

Appendix B: References ...... 1

Appendix C: PhRMA Implementation Flowchart ...... 1

1.0 EXECUTIVE SUMMARY AND INTRODUCTION

FDA has authority through the Food and Drug Administration Amendments Act of 2007 (FDAAA) to require (or order, in some cases) safety label changes (SLCs) for drugs or biologics about which new information has become available that indicates a need for a change to labeling.

Given that FDA believes that the risk to human health can be reduced by changing existing labels, FDA is concerned that these labeling changes be implemented in the production process as expeditiously as feasible. However, FDA is uncertain about what implementation timelines are feasible. Additionally, the extent to which decision factors in setting timelines can be made consistent across many different types of drugs and biologics, will make it easier for FDA to enforce the approved labeling change implementation.

FDA has preliminarily outlined four possible implementation scenarios, each of which would require a different implementation timeline as well as different costs to manufacturers and the potential to delay patient access to necessary medicines. These scenarios are:

1. New labeling is packaged with next manufactured batch of drug. 2. New labeling is packaged with next drug shipment (may require relabeling and repackaging of inventory) 3. New labeling is packaged with the next drug distribution (may require recall from wholesaler) 4. New labeling is packaged with all drug product sold to end users after a specified date (may require a recall at the pharmacy/hospital/provider)

ERG investigated how industry currently implements SLCs to assist FDA in determining feasible implementation scenarios and associated timelines. The focus of our investigation was to determine baseline practices and the potential impacts of changes to those practices. ERG also investigated the differences between manufacturers who have been able to implement SLCs on an FDA-set deadline and those who requested additional time to implement SLCs. Additionally, ERG summarized comments that were submitted by industry in response to a Federal Register Notice requesting information pertaining to SLCs. ERG followed up on these comments and gathered additional information on typical timelines, but also focused on specific issues that manufacturers encounter when implementing SLCs when the process is less straightforward (e.g., special printing requirements, such as foil packs, and package size changes, which sometimes result in the need to retool packaging lines).

In identifying the current SLC implementation practices in the industry, ERG has established that there are a number of steps in the process between the issuance of an FDA notification letter that an FDAAA safety labeling change (SLC) is required and the receipt of revised labeling by the end user of the product. The steps to implementing SLCs, whether in packaging, in shipped product, or in products further down the supply chain, are somewhat consistent throughout the industry. The most complex portion of the process occurs in the manufacturing establishment. The implementation of an SLC at a manufacturer consists of many steps and there can be some wide variations in elapsed time between steps. This variation depends primarily on demand for the specific product and, in some cases, in the manufacturer’s perceived priority for making the change to labeling. The steps involved and the order in which they generally occur are:

1. FDA approval of a SLC 2. Review, proofing, and aligning the manufacturer’s labeling files with FDA-required language 3. Posting revised labeling on corporate websites

4. Converting text files to Structured Product Language (SPL) and submitting this labeling to FDA and other information repositories 5. Artwork/typesetting to prepare labeling text for printing (includes proofing steps) 6. Printing (includes proofing steps and manufacturer approval steps) 7. Delivery of new labeling to production line 8. Incorporating new labeling into packaging 9. Distribution of packaged product into manufacturing inventory/distribution centers 10. Distribution of product to wholesalers/distributors 11. Distribution of product to retailers, health care services and providers 12. Distribution of product to end users

Figure 1 shows a flow diagram of this process and the steps involved.

Based on timelines discussed with manufacturers and other parties involved in SLCs, including contract printers, contract packagers, and a leading labeling and regulatory expert, ERG determined that high priority SLCs (as defined by manufacturers) that do not involve major changes to PI or PPI formats or multiple levels of packaging (e.g., outer cartons) can be implemented in packaging in relatively short time frames (usually within a few months, if the drug is packaged frequently When those labeling changes get to end users (hospitals, patients) is determined largely by how often the drug is packaged and the size of manufacturer inventories. Manufacturer inventories are a function of how often the drug is packaged and the safety stock that the manufacturer determines is necessary to prevent shortages. Inventories at wholesalers and retailers tend to be much smaller and less variable.

ERG determined that the most feasible implementation scenario is one specifying a deadline for revised labeling to appear electronically on manufacturer websites, in other forms such as Dear Healthcare Provider letters, and in the packaging at the next packaging run after a certain date. FDA might be able to set a generalized date for revised labeling to appear in packaging (for example, 4 months after FDA approval), which most manufacturers would be able to meet for most FDA-required labeling changes, subject to a few exceptions that occur very rarely. A scenario requiring revised labeling in shipped product would be very difficult for FDA to manage because it would be nearly impossible to set a general timeframe that most manufacturers can meet without having to ask for an exception or risk repackaging or recalls and/or potential drug shortages. This would mean FDA would have to work with each manufacturer to gather information on production cycles and inventories as well as any unusual issues that could further delay the revision process. Any scenario that affects products that are beyond the direct control of the manufacturer (e.g., sets dates for shipment from wholesalers or dates to end user) risks recalls and potential drug shortages and is even more difficult to determine on a case-by-case basis than the “in shipment” scenario.

Rough timelines based on all data collected are summarized in Table 1.

2 Figure 1. Steps in SLC Implementation Process

Post to corporate website No errors No errors

Quality checks Errors Revise labeling found Errors Found FDA approval Make PDF version

No errors No errors Schedule labeling change Quality checks Artwork [a] Quality checks for packaging production Make new/revised word processing Errors found Errors found Printer document to No errors match FDA text [a] Revise labeling Revise labeling Quality checks Errors Errors Found No errors Found No errors Errors found

Revise labeling Quality checks Revise /create XML/SPL Errors found No errors Errors found

Product inventory and/ Revise labeling or distribution centers Added to labeling inventory and Errors Packaging run integrated into production scheduling Found No errors Wholesalers

FDA Other databases Key: Revising and proofing label Pharmacies Artwork Put file on corporate website SPL End users Printing Production Distribution [a] e.g., Quark or other publishing software, sometimes this step is also contracted out to the printer but the same number o f review steps would be expected.

Table 1. Elapsed Time for Steps in the SLC Process after FDA Approval

Very High Priority SLC (No Typical SLC with No or Issues Minor Issues Typical SLC with Major Step Encountered) [a] Encountered Issues Encountered [b] In regulatory review/posted to <1 week 1-2 weeks 1-2 weeks company website Artwork <1 week 1-2 weeks 1-2 weeks 1 week (concurrent 14 days (concurrent with 14 days (concurrent with SPL uploaded with artwork) artwork) artwork) Additional time None to up to 4 additional 4 to 8 weeks; rare required for issues None weeks instances, up to 16 weeks encountered <1-4 weeks (depending on Printing/QA printer, relationship 4-6 weeks 4-6 weeks with manufacturer and queues) Potential timeline 2-6 weeks (smaller from FDA approval to 12-16 weeks; rare instances firms may need up 8-12 weeks ready for packaging up to 24 weeks to 6 weeks) run Packaging run Varies, typical is Varies, typical is quarterly Varies, typical is quarterly frequency [c] quarterly Manufacturing Varies, typical is 3 Varies, typical is 3 to 6 Varies, typical is 3 to 6 inventories to 6 months months months 1 week to 1 month 1 week to 1 month 1 week to 1 month Wholesale inventories typically typically typically 1 month to <2 Retail inventories 1 month to <2 months 1 month to <2 months months [a] While this is a possible timeline, due to potentially significant inventory losses and coordination costs, this implementation timeline could impose high costs on the manufacturer. Small manufacturers might not be able to count on shorter time frames for printing. [b] Major issues are challenging circumstances that the manufacturer encounters such as unusual printing media, major and complex PI changes, need to change package size, etc. [c] Packaging runs might be made as frequently as weekly to as infrequently as every few years. Manufacturing inventories are sized on the basis of the packaging time frame plus additional safety stock to ensure product will not be in short supply at any point before the next packaging run is scheduled.

The remainder of this document summarizes all of the information we obtained from our contacts with various entities involved in SLCs or the drug supply chain and comments received on an FDA Notice to the Federal Register requesting information on SLC timelines and issues.

Section 2 discusses the steps outlined in Figure 1.1, the elapsed time needed for these steps, labor requirements and other costs for handling SLCs within these steps, shortest feasible elapsed time for each step up to the printing process, and other pertinent information, such as impediments to meeting accelerated schedules for printing or other portions of the process. The section focuses on the general

timelines associated with the majority of SLCs. It presents the typical times reported for accomplishing the various steps needed to implement SLCs (under the various definitions of implementation) and discusses expedited times that can be accomplished.

Section 3 summarizes information obtained from calls to other entities who also play a role in making changes to SLCs, disseminating information, or distributing the products affected by SLCs.

Section 4 then investigates specific SLCs applying to quinolones and another specific drug product (not named for confidentiality) to determine how certain manufacturers with specific products and issues dealt with a requirement to implement the labeling change in shipped product.

Section 5 discusses the key exceptions to the typical timelines that were developed in Section 2. This section builds on comments provided by manufacturers and others that were submitted to the docket FDA-2011-N-0849. Such exceptions include SLCs requiring changes to text on unusual printing media, changes to pharmaceutical sizes or numbers of inserts, multiple levels of labeling and multiple affected SKUs, changes to packaging sizes, engineering changes to packaging lines, coordination issues with international labeling requirements, coordination issues with other FDA offices (e.g., Risk Evaluation and Mitigation Strategies program), and other challenges to meeting a typical SLC timeline.

Section 6 digests the preceding information and provides some key insights for how FDA might work within the typical and unusual timelines and various implementation choices to manage the process of SLC implementation.

ERG also provides three appendices. Appendix A provides a more detailed summary of comments submitted than those provided throughout the main body of the report. Appendix B provides the names and organizations contacted during the course of this work, including those who commented on FDA’s Notice and were selected for follow-up telephone calls. The flowchart provided by PhRMA in their comments to FDA’s Notice is provided in Appendix C for reference. It is similar to the ERG chart but also includes the steps when an exception occurs and their estimates of time required for each step.

2.0 TYPICAL SLC TIMELINES AND TASKS

To help FDA identify SLC timing issues, procedures usually followed, and exceptions to those procedures, this section of the report presents the typical timelines and tasks involved, as specified by manufacturers, in making changes, both electronically and in the physical labeling itself. Drug labeling includes:

 Package Inserts (PI) – Labeling that lists drug information for healthcare professionals  Patient Package Inserts (PPI) – Labeling that lists drug information for consumers  Medication Guides (MG) – Labeling that is required by FDA for some drug products to be given to the patient at the time of dispensing  Carton and Container Labels – Labeling on the physical packaging of drug products

Discussions with manufacturers have been divided into several types of generalized cases. These generalized cases can be considered baseline cases. They focus on current timelines used for implementing labeling and labeling changes for typical products. They include a generalized case of a high priority SLC, a generalized case of a drug launch, and, briefly, a generalized case of a low priority SLC. The drug launch case is included because drug launches are among the highest priorities for getting labeling ready and into packaging and thus this case indicates what manufacturers can achieve when a packaging run is standing by and all parties in the firm and any contractors, such as printing firms, are on

alert. Section 2.1 identifies how manufacturers set priorities when they do distinguish between low and high priorities, while Section 2.2 presents the discussion of the two levels of SLC priorities and the case of a drug launch, used to illustrate what can be done under best-case conditions, assuming no product in the supply chain.

2.1 SLC Priorities Set by Manufacturers

Because priorities can have an effect on the timeline, it can be useful to understand the extent to which manufacturers define high priority SLCs. According to the contacts made, most manufacturers prioritize SLCs, with a few exceptions. One such exception, a manufacturer who primarily manufactures generics, does not usually prioritize SLCs but has a standard operating procedure (SOP) requiring revised printed labeling to match the branded labeling to be ready to go in packaging in 30 days after they obtain the NDA sponsor’s revised labeling via the generic manufacturer’s drug information vendor.1 This manufacturer is usually aware of a change within a week after the revised labeling is obtained by their drug information vendor (the manufacturer receives updated information from their vendor on a weekly basis). Therefore, the manufacturer effectively assigns all SLCs equal priority. However, the manufacturer did indicate that an FDA-required change would be given a top priority within their standard operating procedure (SOP) of a 30-day turnaround on labeling changes (printed and ready for production). As a generics manufacturer, they are obligated to match the branded label exactly, no matter what the change is. Their general lack of prioritization perhaps reflects the nature of their business. More information on differences between branded manufacturers and generics manufacturers is presented in Section 5.8.

The manufacturers who prioritize SLCs indicated the following general guidelines for classifying SLCs. Most also indicated very strongly, however, that all SLCs are prioritized case by case and that within the generalizations discussed, there are often exceptions. The generalized priority setting schemes mentioned by manufacturers include the following:

 Examples of high priority SLCs mentioned by manufacturers: o All FDA-required changes o Many FDA-required changes, but not necessarily all o Any SLC that changes who takes a drug (a new contraindication) or how it is taken (a change lowering the maximum dose) o Addition of a black box warning o An SLC with a perceived liability risk for the company  Examples of low priority SLCs mentioned by manufacturers: o A minor change in a side effect profile of a minor side effect (e.g., a change from 1 percent to 2 percent for those experiencing nausea) o An extension in shelf life (e.g., to increase it from 1 year to 18 months)

Between these two generalized priorities lie a large portion of SLCs that would be prioritized on a case- by-case basis. For example, although a minor change in a minor side effect might be low priority, an SLC might need to be judged as to whether the change is minor and whether the side effect is minor. A major change (however that is decided on) in a major side effect (also subjective) would have to be considered

1 ERG is not certain exactly why the generics manufacturers we spoke to seemed to be able to place labeling in packaging generally more quickly than manufacturers of branded drugs, but it could be the result of a limited sample. The generic manufacturers we spoke with, however, seemed to have well-established procedures to expedite the process, whereas not all branded drug manufacturers have established such clear lines of responsibility and procedures. Having SOPs in place for handling high priority SLCs seems to be a key distinction between manufacturers who are relatively fast in implementing SLCs and those that seem somewhat slower to implement.

on a case-by-case basis before the manufacturer determines whether it rises to a high-priority level. These decisions are often made by committees. For SLCs that are not clearly high or low priority, the decisions made by manufacturers could vary.

It is important to note, however, that if FDA were to require all SLCs to meet the most expedited schedules discussed in the high priority SLC case study, scheduling conflicts could arise. The expedited schedules discussed in the high priority case work because usually very few SLCs are considered to need such expedited handling at any given time.

In addition to the case study of a generalized high priority SLC, ERG also presents a case study of a generalized low priority SLC to indicate the current timelines for implementing a labeling revision with no special procedures for expediting printing or otherwise making changes to “business as usual.” After these generalized case studies, which merge together discussions with a number of manufacturers to create a “typical” case for a conventional drug on three types of timelines (high priority, drug launch and low priority), ERG provides, in Section 3, information obtained from calls to other entities who also play a role in making changes to SLCs, disseminating information, or distributing the products affected by SLCs and in Section 4, case studies involving specific SLCs for two types of products. These SLCs covered quinolones and another specific drug product.

2.2 Baseline Case Studies of Labeling Timelines

ERG presents three generalized case studies to highlight the range of usual schedules for SLCs depending on priority. These are: 1) a high priority SLC, 2) a new drug launch (which is used to illustrate what might and might not be possible for a high priority SLC), and 3) a low priority SLC. (To allow for confidentiality, the individual companies contacted by ERG are not cited individually in this section, although those companies who commented on FDA’s request for information are named. Appendix B lists companies who commented.)

The highest priority labeling implementation set by manufacturers, and the one that is easiest to expedite, is the labeling for a new drug launch. Because this labeling must also be approved by FDA before a new drug is introduced to the market and because changes might be necessary when the final approval is received by the manufacturer, ERG has prepared a generalized case study of labeling changes during a new drug launch. It is clearly in the manufacturer’s best interest to get a new drug launched in as short a time as possible after FDA approval. Thus, this case study of a new drug launch is presented as an example of what the manufacturer can do with what it likely perceives as the highest priority for getting labeling ready and into packaging (although it should be noted that in this case the manufacturer generally does not have to manage the complications associated with minimizing product and labeling inventory loss).

ERG first presents the steps taken and the timelines involved in a generalized high-priority SLC. The basic steps can be the same for a high priority SLC as a drug launch. However, ERG wishes to explain the full extent of the steps relative to SLCs rather than those for a drug launch, so the steps and timeline of a high-priority SLC are discussed first.

Next, ERG focuses on the timelines achievable during a new drug launch. This discussion covers the same basic steps as those discussed for the high priority SLC. It also discusses the major differences between the high priority SLC process and the new drug launch that allows some of the steps to be shortened in the drug launch relative to the high priority SLC. These differences can make it difficult to expect the same brief timeline for some of the same high priority SLC steps.

Finally, ERG presents the timelines involved in a generalized lower priority SLC. ERG is not considering timelines of lowest priority label changes that are not SLCs, (e.g., correction of a “typo” unrelated to any safety issue). These low priority changes are usually accumulated and implemented when an SLC is undertaken or when a number of minor, non-SLC changes have accumulated and the labeling inventory needs to be reordered.

For the most part, the case studies below are developed for a generalized conventional drug. However, several manufacturers who manufacture both conventional and biologics indicated that the timeline and steps to printed labeling are identical.2

2.2.1 High Priority SLC

2.2.1.1 Receipt of FDA-Approved Language, Review, and Website Posting

Generally, the manufacturers contacted have a well-defined process for labeling changes, which is particularly necessary for large, multi-national drug firms. The manufacturer is often aware of SLCs that will be required by FDA ahead of the approval date and the information is provided to a committee that determines the priority the SLC will have. The priority decided on sets the general timeline of the labeling change implementation.

For the highest priority changes, such as certain FDA-required changes, if the manufacturers are aware that an FDA approval is imminent, for the most critical of such changes, the process of implementing a change can be very short. The timing outlined below, however, implies that all necessary personnel are all treating the SLC as their top priority following final approval, including those involved in artwork, printing, data translation, etc.

The first step after the approved labeling language is received from FDA requires the labeling files to be proofed against the FDA-required language to determine the changes to be incorporated into the manufacturer’s version of the labeling. Typically, for a high priority change, the approved language is immediately and very carefully proofed against the version held by the manufacturer, with changes highlighted and made in the electronic version held by the manufacturer. The proofing can be done manually, although some manufacturers also use electronic document compare in addition to human proofreaders to reduce proofing time (Fontaine, 2011). As discrepancies are caught in proofing, additional rounds of proofing are then made to ensure that all changes are caught. This process can involve several proofreaders working together or separately. The more extensive the changes, the longer this process can take. Reviews take longer, and the potential for errors (and, thus, more rounds of proofreading) is greater.

Before the labeling proceeds to other stages, it needs review for approval by one or more higher-level executives in regulatory affairs or similar departments. At a minimum, this step can take as little as 30 minutes to go from an FDA approval to a label posted to the company website (e.g., when the company is aware that an FDA approval is imminent, when the labeling change is not too extensive, and all departments involved are on alert, which are situations similar to the new drug launch scenario). One manufacturer noted that high-priority SLCs can be posted to the company website (e.g., PDF) within 24

2 The major difference between biologics and conventional drugs are most likely the frequency with which they are typically produced, the size of the batches, and thus, their inventory sizes. Shorter shelf lives of biologics, however, may limit inventory sizes as well. Additionally, because of manufacturing complexities, biologics can be in short supply, and that could lead to reduced flexibility in meeting implementation dates beyond those designated as “in packaging.”

hours and that even extensive changes can be managed in this time frame. Another noted that their fastest time was 4 hours for special circumstances. Such a turnaround might require 3 proofreaders, 8 hours each, but these proofreaders can work concurrently (along with use of electronic document compare technology).

Other manufacturers have noted that high priority SLCs might be posted to their websites from 24 to 72 hours after approval (PDFs, generally, not SPL versions). Manufacturers reported a range of about 1.5 to 3 days to a final approved set of labeling files ready for website posting and other labeling activities. Any issues with timing at this step mostly involve the complexity of the changes and how much inter- establishment coordination might be needed (for example, a large multi-national firm might need to coordinate labeling at several U.S. facilities as well as coordinate with regulatory affairs personnel in Europe or Asia). In addition, since companies will continue to proof a label until mistakes are no longer found, time spent on this task can also be affected by the use of electronic readers and the quality of proofreading.

2.2.1.2 SPL Conversion and Artwork

As soon as the electronic labeling files are approved, they can be sent to several places (in addition to uploading to the website). These include to an artwork department or contract typesetter (or in some cases to the contract printer, some of whom have their own artwork departments) for artwork/typesetting and to a SPL department or contract SPL conversion firm. Some manufacturers have onsite SPL conversion capabilities, but this tends to be the exception (Fontaine, 2011). All manufacturers ERG contacted indicated that they meet requirements to upload SPL files to FDA and DailyMed in 14 days or less.

The artwork step can be time consuming if changes to formatting are required, if many SKUs are affected, or if other levels of labeling (outer containers, etc.) are affected. A high priority change with no major reformatting can be completed by the artwork department or contractor in several days. The range reported by the manufacturers was 1 to 3.5 days. Major reformatting of a PI could, however, take as long as a week or two, for example, if a PI’s text size increases substantially, a MG must be typeset and added to the PI, several levels of labeling are affected and many SKUs are affected, each with different labeling requirements, or if the new formatting requirements have not yet been incorporated in the labeling (see Section 4 for more information on major PI changes and how these changes can affect timing). Manufacturers indicated that reformatting to meet changed format requirements (e.g., to meet the format required by the Physician Labeling Rule [PLR]) would need to be done during the SLC process.

The artwork step also includes multiple rounds of proofreading and additional approval of final copy, especially if a contractor is used. The contractor often performs internal proofreading, with final copy going back to the manufacturer, who does additional proofreading. Thus, using a contractor for artwork introduces extra rounds of proofing (Fontaine, 2011). However, the manufacturers ERG spoke with generally use an in-house art department. Once the artwork is approved at the highest level, it can be sent to the printer.

At this point in the process, elapsed time from FDA approval can be as short as 2.5 days for a high priority SLC with relatively minor changes to text. Elapsed time for more complicated changes might involve up to perhaps 2 to 2.5 weeks from the FDA approval (assuming no package sizing complications; see Section 5).

2.2.1.3 Label Printing

Most manufacturers contacted use outside printing contractors for most printing applications, although some have some in-house printing capabilities. For example, one manufacturer had a line that packages

and prints blister packs in one process. Most indicated that they had multiple contracts with printers, but tended to use one or two primarily. Generally, if an SLC involves a change to outer packaging labeling, this change will often involve two separate printers, one for the change to the PI and one for the change to the outer labeling; printers tend to specialize. The remaining contracts are in place as a backup. Manufacturers rarely switch printers because it takes time and money to research a printer and get them qualified to produce labeling.

At the printing department or contractor, the printer reviews the changes to the labeling, determines any changes to the printing/folding process that might be required relative to the previous formatting of the labeling, makes a printing proof, possibly does an internal proofing to make sure no lines were dropped in the process, sends the proof to the manufacturer for final approval, and, when given approval, makes the labeling run. For very quick turnaround, the printer might produce just a few days’ worth of labels to provide immediately. The printer would then follow up with the remainder of the requested labeling. The run usually covers the number of units in the next packaging run, as well as some labeling for a manufacturer’s labeling inventory.

Although most of the large manufacturers indicated that their printers could turn labeling around in 3 to 4 days, one contact, a contract packager, indicated that many of their clients who were small to medium size firms would not have enough business with a printer to request shortened printing times. Several manufacturers indicated that the usual printer turnaround time is about 2 to 3 weeks. Others, such as the printers associated with the contract packaging operation discussed above, require a 4- to 6-week turnaround, with little leeway granted to any but the largest of their customers.

Therefore, the fastest turnaround likely for an SLC at a major pharmaceutical firm (i.e., one with their own printing department or the type of relationship with a contract printer that could move a priority SLC to number one priority for that printing contractor) could be as little as 2 to 4 days. However, a small manufacturer might be faced with a 2- to at least a 4-week turnaround as a best-case priority printing schedule.

Printed labeling can, therefore, be available under the best of circumstances after FDA approval in as little as 5.5 days, assuming all steps in the process can be accomplished in the shortest time frame possible. A more typical high priority schedule, and one that allows for more complexity in the process, including any formatting issues or simple outer package labeling change needs (without package size changes), and possible consideration for small firms, might include: 1 week for text approval, 1 week for artwork, and 4 weeks for printing, for a total of 6 weeks from approval to printed labeling available for use in packaging.

Commenters to FDA’s notice (e.g., Hospira) have noted that there is a delay between receiving printed labeling and implementing in production to allow for quality checks of the materials. Under an expedited schedule where the packaging run is to be made when printed materials are received, a few additional days might need to be considered in the timing to allow for these quality checks.

2.2.1.4 Implementing Printed SLC in Production

The next step in the SLC implementation process is the most variable in timing. Drugs are typically produced in batches on a particular schedule dictated by demand for the product, and, in some cases, the complexity or expense of the manufacturing process. Most manufactures do not stockpile unpackaged drugs for any length of time, nor do they usually package immediately inline from a manufacturing run to a packaging run in one process. Sometimes the drug is packaged in bulk and sent to another facility for packaging or to a contract packager (where the bulk drug might be inventoried for some period of time, with inventories drawn down when an order to package is received).

Packaging cycles might range from once per week to once every few years. Manufacturers identified quarterly packaging runs as fairly typical. Packaging cycles less infrequent than twice per year are less common for conventional drugs (i.e., non-biologics) than those made more frequently (Fontaine, 2012). Therefore, a requirement that revised labeling appear in the “next packaging run” after a certain date could mean the revised labeling would be in the packaging in less than a week after that date to more than a year depending on the usual packaging cycle for the drug in question and at what point in that cycle the drug is in.

2.2.1.5 Packaged Product with SLC Enters Manufacturer's Inventory/Distribution Center

Like packaging production cycle times, inventories can also vary widely. Some manufacturers mention that 3-6 months might be typical. Others have much smaller inventories. For a drug packaged on a 3- month cycle, the inventory after the packaging run is going to be at least 3 months, with several more weeks to months “safety” stock (additional stock maintained to ensure shortages do not occur). Thus the packaging schedule has a relationship with the size of the inventory (in time terms). Timelines for inventories throughout the remainder of the supply chain are discussed in detail in Section 3.

2.2.2 New Drug Launch Timeline

With a new drug launch, the manufacturers generally work with FDA for some time on the exact wording of the labeling, negotiating back and forth. This negotiation and preplanning occurs in some instances during the SLC process, but there can be less warning for some SLCs. During a drug launch, when FDA and the manufacturers are getting close to an agreement, it is often the case that only minor changes, or even no changes, are made to the final wording delivered by FDA in their approval. Therefore, there is often the opportunity, after FDA approval, to shorten many of the steps to a final printed set of labeling. The manufacturers can have everything in place ready to go for the drug launch. All personnel are on alert waiting for the final approval. Therefore, at this stage, the lower value in the ranges of time seen for high priority SLCs is likely to apply in the review and approval step.

In some cases (particularly those with no changes to final labeling), one contact indicated that the labeling pdf could be posted on the company’s website in 30 minutes, although within several hours to 24 hours is more typical. A major difference with drug launches, too, is that some of the manufacturers indicated that they will sometimes print labeling before final FDA approval (“printing at risk”), which then means that as soon as the approved labeling is reviewed and confirmed not to have changed from the manufacturer’s labeling files, the packaging run can begin. In some cases, the drug has been packaged, waiting for the PI to be inserted. One manufacturer also indicated that for some launches, the drug might be packaged with a PI “at risk.” If a change is necessary, repackaging is done.

This is very different from the situation with an SLC. Even with a high priority SLC, the manufacturers had not repackaged any drug because of an SLC (and an SLC had, to their knowledge, never prompted a recall of any sort) or had noted it had only occurred perhaps once to their knowledge. Therefore, the availability of revised labeling well before the next packaging run generally does not accelerate the introduction of the revised labeling into the supply chain (except in the case of some specific SLCs, in which FDA required all labeling to be in a shipped drug by a specific date—see the specific SLC case studies in Section 4).

A manufacturer indicated that in some cases, drug lots can begin shipping in 24 hours. ERG also spoke with two contract operations who noted that for a drug launch, some of their customers label and package the lot “at risk.” If an SLC does come through from the NDA sponsor at the last minute for a generic launch or if FDA changes the wording for a new drug launch, these contractors do repackage the lot

(these sources indicated that repackaging takes 2 days to about a week; the total delay in the launch could add up to a month).

If there are minor changes, again, the lower time ranges seen for high priority SLCs will apply. Only very rarely do more extensive changes push times over those seen at the lowest end of the ranges for high priority SLCs discussed earlier. Furthermore, for drug launches, some manufacturers pay for contract printers to stay idle while waiting on the artwork, which means even the 3 to 4 days that it might take to print a rush high priority SLC might be reduced to as little as one day. A drug launch with changes to labeling, then, might take as little as 2 to 3 days.

Another difference between a drug launch and a high priority SLC is that no printed labeling inventory or packaging is usually lost (unless labeling is printed at risk and/or the drug is packaged at risk). This loss of labeling inventory adds to the cost (or timeline if manufacturers opt to use up inventory) of an SLC vs. a drug launch.

The biggest difference between SLCs and a drug launch, however, is that the packaging run is made immediately when printed labeling is delivered (if it hasn’t been already packaged), and the first lots are shipped without any delays in inventory. Thus, the new drug can reach end users in a matter of days to weeks, not months or years for revised labeling associated with an SLC. An SLC might work its way through months of remaining time until the next packaging run and then sit for several months or more in inventory. Without expensive measures (such as repackaging, inventory destruction, and/or recalls) most SLCs could not be distributed to end users in the same time frames.

The new drug launch scenario, therefore, serves only as a measure of absolute minimum times from approval to printed labeling, assuming that 1) the manufacturer has some warning of an SLC and all or nearly all labeling changes have been incorporated by the manufacturer prior to FDA approval 2) the reviewers who review and approve final text have the SLC assigned as top priority, art departments and printers are standing by for any last changes, and maximum rush charges are applied throughout the steps (where applicable). Rush charges might also include paying the printing contractor’s time to keep presses on idle waiting for the approval, although some printers do not charge for rush orders or require a timeslot reservation for competitive edge reasons.

2.2.3 Low Priority SLCs

For drugs packaged frequently or with a short time frame before the next packaging run, the difference between a high priority and low priority SLC emerges. In these cases, a drug with a high priority SLC would most likely be packaged with the revised labeling before a drug with a low priority SLC assuming the same date of approval. For a low-priority SLC, some manufacturers noted that several weeks might elapse until the revised labeling is posted to the website and uploaded as SPL to FDA and DailyMed. At this point, the manufacturer might determine the packaging run at which the revised labeling might appear. The scheduled date of that run will then determine the remaining portions of the schedule for artwork and printing.

Some manufacturers indicated that low priority SLCs would probably not be printed for 3-6 months or longer. A few pointed out that even if the printing could be done before the next packaging run, there is some resistance by the production/packaging departments to discard major portions of labeling inventory, so additional packaging runs might be made before the new labeling is used. The individual in the steps between providing the labeling files to artwork and providing the typeset labeling to printing would not necessarily be different, but elapsed time is generally longer, with downtime between each step possible on a non-urgent schedule.

Note that, for drugs packaged infrequently or with long time frames remaining before the next packaging run after approval, the time elapsed between FDA approval and packaging with the revised labeling might not be any different for high priority and low priority SLCs. A SLC for a drug with many months until its next packaging run would not necessarily trigger a rush on label printing even if the SLC were considered to convey information that would place it on high priority if a packaging run were to be made shortly.

3.0 INFORMATION RECEIVED FROM OTHER ENTITIES WITH ROLES IN THE SLC PROCESS

This section summarizes information ERG received from contract printers, wholesalers, distributors, retailers, contract packagers and drug information vendors that helps confirm the timelines presented in Section 2 and provides information on the SLC timeline between when a drug product with an SLC leaves the manufacturer and reaches the consumer, given inventories kept at the distribution, wholesale, and retail levels. As with the general discussion of manufacturers’ timelines, the individual sources are not cited to protect anonymity but are listed in Appendix B.

3.1 Information Received from Contract Printers

Most pharmaceutical manufacturers utilize a third-party printing provider to print product labeling, although a few of the large pharmaceutical manufacturers may do in-house printing (Fontaine, 2012). While SLCs can affect container or carton labeling (e.g., when a MG is added to a product and a statement to indicate this has to be printed on the label), most safety labeling changes affect the PI, PPI, or MG. The MG and the PPI are usually separate pieces of paper, but sometimes are printed on the same paper as the PI. Products are often supplied with one PI and multiple MGs per package. For example, a 90-pill bottle may fill 3 scripts, requiring 3 MGs but only one PI. 3

The pharmaceutical printing industry has consolidated significantly in the last few years. Smaller pharmaceutical manufacturers and generic manufacturers still often use smaller “Mom and Pop” printers. Small printers that print pharmaceutical inserts and outserts, however, are few in number because the printing industry has been consolidating. In addition, the pharmaceutical insert and outsert printing industry is a niche market, requiring expensive, specialized machinery for folding due to the thin, large paper used. This need for specialty equipment makes it especially challenging for smaller printers to compete with larger printers. Larger printers have the capital to acquire the equipment necessary to accommodate different sizes of inserts and outserts, while smaller printers are limited in the sizes that they produce because they cannot afford the same range of equipment.

To learn more about current pharmaceutical printing practices and timelines, ERG consulted four printers. Of these, one specializes in printing pharmaceutical inserts and outserts only, one specializes in printing carton and container labeling only, and the remaining two do both types of printing. Digital printing is often used for container and carton labeling. While digital technology is also available for printing pharmaceutical inserts and outserts, lithography is more common. Lithography is a printing method that utilizes printing plates. Thus, when a pharmaceutical insert or outsert is changed, a new plate has to be created. Also, if different colors are used on an insert or outsert, inks have to be changed on the machines before printing. Even so, the cost of new equipment and GMP qualification requirements to do digital printing make it less economical than continued use of lithography. Lithography also runs faster than other printing methods for large printing requirements. Color changeovers for lithographic printing are fairly infrequent because inserts and outserts are usually printed in black and use a minimal number of colors, if any. Some printers, however, will use digital technology for pharmaceutical inserts and outserts

3 PIs, PPIs, and MGs will be collectively referred to as pharmaceutical inserts and outserts (which are glued on the outside of packaging) from here on, unless it is necessary to distinguish them from one another.

if the order is very small or if there are lots of complexities (many colors or a label that is frequently changing) that make lithography cumbersome.

When changes are made to any pharmaceutical labeling, many manufacturers do their own artwork, approving layouts and proofs before release to the printer. Based on these documents, the printer creates their version of a proof and sends it back to the manufacturer for final approval. Some manufacturers, often smaller ones, also utilize the graphic artist at the printer to format the artwork from a text document, which is then sent back to the manufacturer for approval before printing. The printer usually receives all documentation electronically, either through email or discs. Once final approval of proofs from the manufacturer is received, the labeling is ready for printing.

The printer creates a proof for the manufacturer in about one to two hours. Proofs are manually checked by staff, in addition to conducting an electronic document compare. A printing run can be started as quickly as one to two hours after getting approval on the proof from the manufacturer, with the first shipment of inserts available to the manufacturer in 24 hours. Other shipments then follow, sometimes 2 to 3 per day. This approach is often used for drug launches, with the first shipment considered the “launch lot.” The timelines for this process are similar for container and carton labeling. One printer completed shipments of 12 different container labels in 24 hours as a rush-job. Printers can also print labels in advance before final approval from FDA, known as at-risk printing.

Printers can print and fold 5,000 to 12,000 inserts per hour. Runs are usually tens of thousands to one million inserts and more. One printer noted that they can ship 500,000 PIs in 24 hours. Many printers operate on a 24 hours a day/7 days a week availability and can turn around a very urgent order in a one to two-day timeframe. The standard lead time, however, is two to three weeks, according to two of the printers contacted, although it should be noted that manufacturers have noted that it often takes an average of 4 to 6 weeks to receive product back from printers.

Some printers allow reservation of a time slot, whereas others accommodate any rush request. If a manufacturer is in a rush to approve labeling, they will get the PI approved and printed first since the MGs are printed on smaller paper and can be printed faster. In some cases, manufacturers have also noted that they may need to switch to another printer that can accommodate them if the printer is booked up. Surcharges for rush jobs are variable. Some printers do not customarily charge extra unless the job requires them to be late on another delivery or when they have to work on days that they are not open. Others do not charge extra, regardless of the circumstances. Also, rush charges may be waived if the customer has significant business with the printer. If rush charges are incurred, they usually are only a few thousand dollars.

Usually, increases in insert or outsert size can be easily accommodated. Printers and manufacturers will try to anticipate size increase and plan ahead of the printing for the new template and folds. However, as noted earlier, some of the smaller printers of inserts and outserts may not have all the equipment to print and fold larger paper. Thus a larger insert may force manufacturers to switch to another printer who can accommodate the larger label.

Some printers maintain inventories of labeling for mature products for their customers. On such products, the probability of changes to the PI labeling is low and the runs are small. For example, if the manufacturer orders 1,000 PIs, the printer might print 2,000 as it is more economical to use the presses that way. Printers do not have a lot of warehouse space, however, so this is not done frequently. Other printers do not keep any inventory at all and ship immediately to manufacturers or contract packagers.

Costs per PI are relatively insignificant, from less than one cent per label to a couple of cents per label. Rush charges can be incurred (around 10 to 20 percent), depending on the company and the size of the

order/other business. The cost for a perforated PPI or MG is slightly higher, by roughly 10 percent over a stand-alone version.

3.2 Information Received from Contract Packagers

The definition of pharmaceutical contract packager can vary depending on what and how they package product. For the purposes of this report, contract packagers are defined as companies that receive product from a manufacturer and package the product as a service to a manufacturer or other company. Also, a contract repackager is a type of contract packager who receives product in bulk containers from the manufacturers and repacks it into (usually) smaller units for resale or distribution to hospitals and pharmacies. The contract packager or repackager may or may not take ownership of the product from the manufacturer and this affects their involvement in the labeling process. Generally, contract packagers operate under two scenarios, although there might be a gray area in which a manufacturer is more involved with the process within Scenario 1 or the contract packager is more involved in the process within Scenario 2:

1) The contract packager puts its own NDC number on the label and handles inspection and approval of the label and works together with the label supplier. The contract packager receives the label from the supplier, verifies it with master specifications from the manufacturer and then sends it to the manufacturer for final approval, after which it is integrated into packaging by the contract packager

2) The contract packager puts the manufacturer’s NDC number on the label. In this case, it is usually the manufacturer who handles most of the inspection and approval of the label and works with the label supplier. The manufacturer gives final approval of the label for use in production and then sends it to the contract packager.

ERG spoke to two contract packagers, one of which only uses the manufacturer’s NDC number and the other who uses the manufacturer’s NDC number as well as their own NDC number on products. For the latter, the decision regarding whether to use manufacturer NDC number is largely dependent on whether the product is distributed under the manufacturer’s label or a private label and is guided by the district office.

Both contract packagers noted that it is fairly easy for them to comply with a request to put a label on or in packaging by a given date. The contract packager that uses manufacturer NDCs only noted that they complied with a DEA-mandated change to outer labeling with approximately 3 months leadtime and they were able to do so easily. The other contract packager noted that they could comply with changes within four months. So the timelines for contract packagers appear to be similar to those for manufacturers who package their own drug product, although in some cases, there may be an additional set of quality assurance checks needed before the labeling is ready for packaging (see below).

The contract packager who uses only manufacturers’ NDC numbers on packaging specializes in repackaging products into smaller bottles using the PI supplied by the manufacturer. The products are generally supplied with one PI per selling unit, but the contract packager makes photocopies of PIs if necessary. Although this contract packager has not had any recalls of PIs by the manufacturer, they did recently institute a procedure to note the date of the last insert change. Other than that, they only receive finished labeling from the manufacturer and do not support labeling changes in any way.

The second contract packager provided information on timelines associated with labeling changes when the contract packager puts their own NDC number on the product and is therefore responsible for labeling. First, they receive the notification of a labeling change from the manufacturer (or contract

manufacturer). The contract packager notifies the label supplier and proofreads the draft (done by a minimum of 2 people). This process usually takes roughly ten days. Once the label is approved and submitted to the label supplier, printing can take another 30 to 45 days. If the company has a large account at the printer, they may be able to reduce this timeframe to 1 to 2 weeks. When the labeling is complete, it goes through a quality inspection by the manufacturer and contract packager and then is released to be included in packaging. This process requires roughly 2 to 3 weeks, after which the product is ready to ship. As noted above, this contract packager typically can comply with changes within four months if all labels are ready and no rework has to be done. There are, however some exceptions. In some cases the manufacturer is involved in actively managing the labeling change process and this involvement can result in additional exchanges back and forth between the manufacturer and contract packager, potentially increasing the timeline by 15 to 20 days. As noted earlier, production of new labeling can be completed by the contract packager in approximately four months.

Inventory loss will vary according to whether the product is bright stock (packaged in volume and labeled as customers draw upon the stock), stored in inventory, or run as part of a campaign (all components for product are received and packaged at once). In the latter case, inventory loss would be minimal since packaging components are not stored in inventory. The first two approaches will have varying labeling inventory loss and costs that are dependent on the amount of packaging kept in inventory. Contract packagers try to stay within 30 to 90 days of packaging/labeling inventory. In some cases, however, as much as 8 months of this inventory have been lost.

Contract packagers package as often as once a week for some manufacturers and at least once a quarter for low demand products. This process is more descriptive of contract packagers that service small to medium sized pharmaceutical manufacturers. The process might take longer for larger pharmaceutical companies because additional review steps and bureaucracy are common.

Some homecare companies also act as repackagers. They get product from the wholesalers and manufacturers and repackage it for their pharmacies in quantities that are easily dispensed at their nursing facilities (e.g., bingo cards, 14 day blisters). PIs are also not relevant at this stage and are discarded during repackaging. Such establishments print the MGs when necessary, but do not do so when medications are being administered by medical staff at long-term care facilities. The homecare company contacted indicated that their main source of information for changes in labeling is First Databank, but they also receive information from manufacturers and FDA. They reported that they typically have an inventory of 2 to 4 months at their pharmacies, while their nursing facilities generally maintain a 14-day to 31-day supply.

3.3 Information Received from Wholesalers/Distributors/Retailers

Wholesale distributors and retailers have a very limited role in the implementation process and timelines of safety labeling changes. ERG spoke with three wholesale distributors, one large retail pharmacy, and one homecare provider that performs a hybrid of distribution and pharmacy services.

In general, wholesale distributors do not repackage or relabel product inventory but honor requests from manufacturers to have new product shipped by a future, specified date. They would also return leftover product to the manufacturer if the manufacturer asks them to only ship new supply as of a given date. In general, most wholesalers can provide pharmacies with product within a day after the order is placed. For those pharmacies in more remote locations, it can take up to two days.

Some wholesale distributors might have a separate group that provides additional services to manufacturers, such as contract manufacturing or packaging services. As part of these services, they might repackage and relabel products. For example, they might replace existing PI on an entire batch (3 to

6 months of inventory) with new versions of the insert before the product goes to the wholesaler. The process is manual and requires unfolding and flattening each PI, as well as maintaining a reconciliation record. Typically, a batch of 10,000 PI swaps can be completed in about two to three days. Sometimes additional information, such as a MG, is also wrapped to products using rubber bands but this is not a routine practice.

When a product needs to be retrieved from the supply chain, the recall is usually initiated from the manufacturer and managed by a third-party contractor specializing in recall services. In cases where the distributor has a group providing other services to manufacturers, they might facilitate recalls as well. Otherwise, the role of the distributor or wholesaler is to assist in the recall process by sending product inventory back and notifying customers. Notifications are often posted through ordering systems because contacting each individual customer is too costly for most. In most cases, product is sent directly back to the manufacturer or recall facilitator by the customer. Wholesalers also go through a process to quarantine their own products before sending them back to the manufacturer. One wholesaler estimated that on average, it might take them one to two days to package product and send it back to the manufacturer, depending on the size of the recall.

The manufacturer generally incurs the cost of the recall with the exception of some possible labor input from the wholesaler or distributor to process any returns. Massive recalls could require overtime but otherwise this labor input would be minimal. Sometimes the recall facilitator sends out a general alert and handles return so that the wholesalers do not incur any cost.

No shortages have been caused by a relabeling initiative. Wholesalers noted that recalls are rarely issued for labeling issue, however, and are usually product-related. None of the wholesale distributors contacted by ERG, however, had ever experienced a recall due to a PI labeling change.

According to two contacts, wholesale distributors maintain small inventories ranging from 5 to 10 days up to a month. This general average also applies to biologics. Inventories partially depend on the demand of the product and whether product can be obtained at a lower price than usual. If a product can be acquired at a lower price, they might stock up 3 to 6 months worth of inventory.

When the product reaches retailers, retail inventories are also short. One large pharmacy retailer noted that they keep 30 to 50 days of inventory, based on an algorithm of shelf life and product demand. Small “Mom and Pop” pharmacies might have smaller inventories on hand, however, due to a lack of storage space. The typical inventory of homecare pharmacies is also small, ranging from two to four months, with a typical inventory of 30 to 40 days. Nursing facilities receive two-week to one-month supplies depending on the typical stay of the patient.

Retailers vary in how they handle safety labeling updates depending on their size and target market. A large retail pharmacy chain contacted by ERG receives safety labeling change updates from a third-party information database vendor once a week. Data on new products are obtained from another third-party information database vendor. Large retail pharmacy chains often have distribution centers that work directly with manufacturers and supply pharmacies for chronic medications and have robust internal recall systems in place. Smaller retail pharmacies might not have this same level of coordination.

3.4 Information Received from Drug Information Vendors

Database information vendors sell drug databases to various healthcare practitioners and prescribers, pharmacies, pharmacy benefit managers (PBMs), government entities (VA, CMS), and other healthcare entities and professionals. The companies that manage these databases have similar systems for

incorporating safety label changes when they become available, as ERG learned from conversations with three of these vendors.

Database information vendors obtain information about safety labeling changes from various sources but mostly from manufacturers. Some database information vendors even get label data before product is approved from manufacturers with whom they have good relationships. Vendors prefer to receive changes in SPL from the manufacturer because the format (versus text or PDF format) is most easily integrated into their electronic systems.

The speed with which data are provided to database information vendors by manufacturers, however, is highly variable. Even though vendors prefer to get data directly from manufacturers, manufacturers vary in their responsiveness and timing. Vendors try to manage this problem by making it easier for the manufacturer to provide them with information. One vendor has a dedicated team to reach out to manufacturers, while another provides a website to manufacturers where label data (including SPL) can be uploaded electronically. Further, although most safety label data is collected from manufacturers, vendors also monitor other sources for labeling changes. In some cases, the manufacturer might also refer them to these sources. These sources include FDA (including CDER and CBER) websites, third-party publications, FDA notices and RSS feeds, Medwatch, and the DailyMed (NLM database). The monitoring process is somewhat piecemeal because there is no central notification system that records changes to labeling. If changes are found, database information vendors will follow up with the manufacturer.

As noted earlier, in order to expedite the process of updating labeling data, database information vendors prefer to receive the data in SPL format as this format is most easily integrated into their systems. One vendor noted that roughly half of the manufacturers provide their revised data in SPL. Each vendor deals with this issue in a different way. One vendor noted that if the manufacturer is expected to take up to 2 weeks to provide SPL, they will ask for the PDF and convert it themselves. This process may take a few days and requires review by the manufacturer when completed. The second vendor obtains SPL by completing a weekly download of SPL from NLM to look for changes. The third database information vendor contacted has an alerting mechanism through a sister company that notifies them of any changes on DailyMed. They receive an Excel spreadsheet with updated sections highlighted. If any changes are found, the database information vendor will contact the manufacturer for further data.

All 3 vendors spoken with emphasized the importance of SPL to their processes. They note that SPL is much less prone to error and could speed up the availability of updates in the future. Moving to a version of SPL where only the updated section need to be submitted would also simplify and speed up processes.

The timeframe for a database information vendor to update labeling information in their systems once they receive the data depends on the health-risk aspect of the change and is judged on a case-by-case basis. Sometimes a few days of research needs to be undertaken to determine the degree of health risk, which can happen in the case of an SLC involving a drug interaction (e.g., to find out how many patients have experienced the adverse reaction described). If the change is only descriptive, it can be done quickly. An urgent safety labeling change critical to patient safety could be integrated in a few hours to a day. One company said that urgent labeling changes of this nature occur roughly 10 to 15 times a year. Priority is given based on level of harm and evidence using input from board certified doctors and pharmacists. For example, the recent change in the indication of Avastin (no longer allowed for treatment of breast cancer) was made in minutes. Editors can take up to one or two weeks for less significant changes.

Once the new labeling data has been integrated and reviewed for quality, changes are made on a daily or twice-daily basis to the vendor databases. The time to when these data become available to the customer varies depending on how often the customer pulls the information. Some customers pull data daily, while

others do so once a week or even every two weeks. If the change was made quickly by the database information vendor and data is pulled daily by the customer, then an important safety update could be received as fast as within 24 hours. Usually customers are not notified of labeling updates although they can be in special cases. One of the vendors contacted by ERG is currently adding a feature to their product that shows customers the date when a change was made to provide this type of service.

4.0 SPECIFIC CASE STUDIES OF SLCS

FDA has required labeling to be in a shipped drug by a specific date in a handful of cases. ERG completed studies of two such cases, the 2008 SLC for fluoroquinolone antimicrobial drugs and another recent SLC where the manufacturer needed to negotiate the in-shipment deadline with FDA to ensure continuous supply of the drug (the SLC is not identified at request of the manufacturer who provided data for the study of this case but from hereon will be referred to as SLC Case Study 2 for easy reference).

In 2008, through its authority under the Food and Drug Administration Amendments Act (FDAAA) of 2007, FDA notified manufacturers of fluoroquinolone antimicrobial drugs that a boxed warning in the product labeling is necessary to warn of the risk of tendonitis and tendon rupture. In addition, FDA also determined that manufacturers of these drugs must add a MG to warn of these possible side effects. FDA requested that revised labeling be available online within 10 days of FDA’s notification and that the revised labeling be reflected in the next printing of the labeling. After January 3, 2009, FDA required revised labeling to accompany shipped product.

ERG contacted three fluoroquinolone manufacturers (noted here as Manufacturers A, B, and C). These manufacturers had written to FDA asking for an extension of the deadline for the SLC described above. Manufacturer A did not respond to ERG’s requests for conversations. ERG received useful data from Manufacturers B and C. In addition, ERG contacted five other companies who complied with the 2008 SLC but did not request additional time from FDA. One of these agreed to participate (noted as Manufacturer D) and provided useful input.

SLC Case Study 2 required revisions to the blackbox warning, indications and usage, warnings, and dosage and administration sections in the PI. It also required the addition of a MG and a separate PPI. Manufacturer E provided ERG with detailed information on the process involved with this SLC.

ERG turned the data provided by the companies noted above into case studies of previous safety labeling changes and the details are discussed below in Section 2.2.1 Quinolones, and Section 2.2.2 SLC Case Study 2

4.1 Quinolones

As noted above, the 2008 SLC for fluoroquinolones required the addition of a black box warning and MG. When a MG is newly added to a product, the carton and container labeling must also be changed to let dispensers know that a MG must be dispensed with the product. This requirement makes this SLC more complex than a typical SLC for some manufacturers with unusual product packaging, as discussed below with respect to the foil pouches used by Manufacturer B for their IV products. Manufacturer D did not have the same timeline challenges and was able to accommodate the SLC within the time frame given by FDA. It should be noted that in both cases, the manufacturers were anticipating the SLC but Manufacturer B noted that, in their case, the necessary infrastructure to accommodate SLCs of this level of complexity was not in place at the time because it was the first of its kind for them and because of the requirement to meet a deadline for the SLC to be in shipped product (longer manufacturing cycles and larger inventories played a role in a need for extending the time frame).

Manufacturer B received FDA approval for labeling October 3, 2008. FDA had given manufacturers three months to implement the new labeling, at which point the new labeling had to be shipped with product. The 2008 SLC affected 14 of Manufacturer B’s stockkeeping units (SKUs). Six of the SKUs were tablets (including bottles and blister packs for hospitals), two were vials, two were oral solutions and the remaining two were physician samples.

After FDA approval, Manufacturer B’s first steps were to identify affected labeling and packaging components. Next, the company reviewed labeling language and created labeling proofs. Manufacturer B sent out letters to healthcare professionals explaining the new PI and boxed warning within the month of October. On November 9th, the manuscript was ready for regulatory review. On November 19th, Manufacturer B began the artwork step and started creating the SPL version of labeling. Manufacturer B sent the SPL labeling to FDA within 14 days. Manufacturer B also placed the labeling on company websites in this timeframe. The artwork required roughly 7 to 10 weeks to complete because of the numbers of SKUs affected and the number of levels of labeling affected. Their contract printer usually requires 2 to 4 weeks for a PI change, but as described below, the timeframe was longer for other affected packaging components. Depending on the SKU, the inventory of this drug also ranged from 8 weeks to 18 weeks and the larger inventories delayed the implementation of the new labeling by several months (e.g., in the case of vials, which are manufactured less frequently, with larger inventories). In total, Manufacturer B needed approximately 6 months to begin shipping tablets, 10 months to start shipping vials, 9 months to ship oral solutions, and 6 months to ship physician samples.

Manufacturer B requested an extension of their timeline due to several factors. These factors included the logistics associated with multiple manufacturing plant locations and the multiple SKUs and labeling components affected, the long leadtime required to manufacture affected product packaging (foil pouches), and the need to increase carton and shipping carton sizes for some products to accommodate the larger insert.

Manufacturer B has three different manufacturing sites for their fluoroquinolone products. Tablets are made in a U.S. location, while IV and oral solutions are made in Europe, and minibags are handled by a contract manufacturer. These three sites all have different packaging equipment, requiring different approaches to the labeling change. For example, a PI used at one of the plants is long with text on the front and back, while another used at another location has a broad rectangular shape. Thus, Manufacturer B had to simultaneously manage changes to layouts on multiple levels of packaging, of different sizes, in three different locations. As a result, they created a team to handle this process because, at the time, they had no infrastructure in place to manage the three manufacturing sites in a coordinated fashion. Manufacturer B notes that they learned from this process and now have a streamlined process in place to expedite any SLCs for this product category. This need for coordination added up to two months to the usual one week time to review, create, and approve proofs.

Furthermore, three of the affected SKUs are packaged in special IV bags called minibags with an overwrap (outer bag) that requires a 16 to 20 week leadtime to produce due to the curing process. The steps in this process are discussed in further detail in Section 5.1 (Unusual Printing Media) below. As a result, Manufacturer B indicated that these products were not ready to implement in production until 6 months after approval, rather than a more usual timeline of 2 months.

The vials and oral solution also required more time because the larger PI required carton size changes, which added 2 months to the timeline. Carton size changes are also discussed in more detail in Section 5.4 below.

Manufacturer B considered repackaging but concluded that it would not save them significant time and it was probably not an option for prefilled syringes and vials.

Manufacturer D did not have the same types of challenges relabeling all packaging components and had little trouble implementing the 2008 SLC for its fluoroquinolone products. A major reason this change was not difficult is that they had SOPs in place that required similar procedures for any high priority SLC, therefore their lines of communication and steps to expedite such a change were already in place. Their labeling department produced proofs the day that FDA provided the final language for the PI change and the new MGs for four products (14 SKUs). Four master word documents were circulated for review and then formatted into 8 print-ready layouts. These 8 layouts represented 4 PIs with the MG included and 4 individual MGs. Some of the affected labeling components that were additional to the PI include bottle labels, carton, hospital unit dispensing cartons, flexibag containers, and carton shippers.

On October 3, 2008, the prior approval supplement containing the draft labeling and MG was approved by FDA. Within 24 hours, the safety labeling change was posted on Manufacturer D’s websites. The internal regulatory review was completed in roughly eight days. The artwork was reviewed in approximately 5 days and approved in approximately 2 days. Printing required about 4 to 6 weeks. The first SKU with revised labeling was available in packaging within 3 months, with labeling available to the consumer within 2 months after leaving the plant. The only issue Manufacturer A faced was that inventory levels had to be depleted for some products, but the manufacturer was able to do this within the timeframe presented by FDA.

Manufacturer C also provided some limited input. The main concern for Manufacturer C at the time was loss of product inventory. They had 3 months of inventory that needed to be depleted. The labeling change was not difficult because they were able to accommodate the change without any size changes to secondary and tertiary packaging. As with Manufacturer D, the company infrastructure at Manufacturer C was also organized in a way that these types of changes could be handled quickly (Manufacturer C, 2012).

4.2 SLC Case Study 2

As noted earlier, SLC Case Study 2 required revisions to the blackbox warning, indications and usage, warnings, and dosage and administration sections in the PI. It also required the addition of a MG and a separate PPI. Manufacturer E provided ERG with detailed information on the process involved in the SLC.

Manufacturer E emphasized in their response that each SLC needs to be assessed on a case-by-case basis and in some cases will require close communication with FDA to prevent unnecessary losses and drug shortages [under a deadline to have the SLC incorporated into shipped product]. The SLC affected a total of 22 SKUs. Each SKU is a drug product in its final packaged configuration; e.g., a SKU equals a XX- pack of X,000 single-use vials. All cartons and distribution cases required a new statement to indicate the addition of a MG and 3 SKUs required an increase in carton size to accommodate the new MG (and consequently an increase in shipping and distribution carton sizes).

Manufacturer E and FDA agreed that the new labeling would be implemented prior to formal FDA approval. The new labeling was posted on corporate websites within 2 business days after labeling was agreed upon by FDA. Manufacturer E uses a centralized website so that when approved labeling is uploaded, it is updated on all Company websites, and promotional emails containing links to labeling are updated as well. A Dear Healthcare Provider letter was finalized in collaboration with FDA and also was posted within two days to the websites. Dissemination of the letter was completed within two weeks of FDA agreement on the labeling.

Manufacturer E noted that there were three SKUs at risk for spot inventory shortages but they managed to prevent this by making batches prior to the commitment date to use the revised packaging and labeling components in production runs. SKUs with higher demand and/or lower inventory were revised first. No relabeling was required and the first revised SKU was at Manufacturer E’s distribution center in 10 weeks from FDA agreement on the labeling. Most SKUs were relabeled within 6 months and all were relabeled within 9 months of approval. Production and integration of new labeling was performed in a staggered fashion across SKUs because resources and equipment to produce packaging and labeling are shared across all of Manufacturer E’s products. Drug product with updated labeling was introduced into distribution as existing drug product inventory was depleted. Thus, Manufacturer E was able to use product inventory and minimize scrap and rework and continued to ensure supply to patients.

Manufacturer E noted that the close partnership with FDA on this SLC allowed the Company to avoid a product shortage and minimize losses while taking steps to revise labeling. ERG also followed up on Manufacturer E’s statement in their implementation letter to FDA that they were also investigating the option for wholesalers to provide new PIs and MGs with each shipment. Manufacturer E reported to ERG that it was not found to be a workable option in terms of timing and feasibility.

5.0 EXCEPTIONS TO THE TIMELINES AND TASKS

As noted above in the case studies of the 2008 SLCs, manufacturers may require additional time when they encounter challenges in addition to the typical labeling revision discussed earlier. These include the following:

. Additional leadtime required for printing on unusual media such as foil pouches and tubes (when immediate container and outer packaging components are affected in addition to the PI), . Increases in PI size, . The addition of a MG, . Increases in carton size, . Multiple levels and versions of labeling, . Managing manufacturing at foreign establishments, . Integration with other regulatory requirements such as REMS, and . Obtaining current labeling by manufacturers of generic drugs.

These challenges are discussed further below.

5.1 Unusual Printing Media

In cases where labeling components other than the PI are affected (such as when a statement has to be added for the addition of a new MG), some packaging components require additional time to relabel. Manufacturers noted that revisions to labeling components other than the PI occur roughly 5 to 8 percent of the time but the impact is significant when it does happen. Some printing changes to additional labeling components such as outer cartons made of cardstock can be handled in parallel with changes to PIs and add minimal time to print all labeling required for an SLC. Of particular concern, however, are immediate and outer packaging components that require direct printing on unusual media. ERG identified two printing media that have very long lead times associated with the printing process: foil pouches and tubes.

Foil pouches have a very long lead time, ranging from 16 up to 20 weeks as compared to the average leadtime of 4 weeks to print a PI. These pouches are used for IV bags and they are made from a three-

layer, pre-printed laminated structure. The foil laminate is converted to individual pouches, which are sealed on three sides. A primary filled IV bag is inserted into the pouch during the final manufacturing process and sealed on the top edge. As shown in Table 2, total time from when the manufacturer has approved labeling copy (i.e., after completion of artwork) to when the foil pouches are filled and ready to go to inventory is roughly 80 business days, or 16 weeks. This timeframe, then, adds 10 to 12 weeks to the usual timeline (from printing to packaging is usually no more than 4 to 6 weeks, and sometimes less).

Printing on tubes also has a long lead time ranging from 12 to 16 weeks because there are not many tube suppliers and substantial lead time is needed for scheduling among the many jobs for which these suppliers are contracted.

Table 2. Example Timetable for Foil Pouch Manufacturing Task Days to Complete Task Specifications and artwork sent and returned to pouch supplier for signoff 7 Purchase order placed by drug manufacturer 1 Full-size proofs provided to drug manufacturer by pouch supplier 7 Drug manufacturer reviews and approves proofs 3 Manufacturer returns proofs to pouch supplier 1 Pouch supplier manufactures engraved print cylinders (one for each color) 15 Printer receives print cylinders, which have been inspected and approved 4 by pouch supplier Outer lay of pouch (polyester) is reverse printed with colors as specified 5 Printed polyester is laminated to middle and inner layers 6 Curing and slitting process is implemented to reduce roll width to size of 6 one pouch Pouches are bundled and packaged for shipping 4 Printed pouches are shipped to drug manufacturer 5 Pouches are received by drug manufacturer inventory system and are 1 sampled Samples are quality tested and approved for use by drug manufacturer 5 Pouches are issued to work orders and IV bags are filled, sealed and 1 sterilized Work order tested and approved for release 9 Total elapsed time 80 Source: Manufacturer J, 2012.

5.2 PI Size Issues

When the text added to a PI from a SLC is significant, the PI sometimes needs to be increased in size. This can occur when a MG is added, lengthy warnings are added, or a larger labeling format is required to comply with the PLR (which can include significant additions to content such as the creation of a Highlights section, extended Patient Counseling Information, and revisions to the Adverse Reaction section). Manufacturers have sample libraries of templates for larger PIs, which can speed up the time because they can use those to produce the new PI (they select the appropriate size and fit the information to that format knowing that existing folding steps will apply and that the existing configurations of the packaging equipment can be used). The artwork takes longer when the PI must be resized and no existing template is available. This situation adds another 7 to 8 weeks to the process (including obtaining product, packaging, and printed material samples to evaluate whether the new PI size fits into packaging and how

it affects line automation, if at all). Impacts that the large PI has on other packaging are discussed further below in Section 5.4.

In most cases, manufacturer use contract printers. The printing and folding equipment at these printers can accommodate many size changes. If a printer cannot accommodate the size change, a manufacturer might need to change to another contract printer (which can also take time to identify). This issue is discussed earlier in Section 3.1 about contract printers.

If a manufacturer does its own printing or folding, an increase in PI size can also require retooling or purchasing new equipment. Sometimes the number of folds required for a larger PI cannot be accommodated by the existing machinery. Retooling occurs when a piece of equipment has to be removed and replaced by another and can take roughly 1 to 2 months. Buying new equipment is a much longer process because equipment needs to be researched, ordered, received, and validated, all while maintaining product supply. This process can take up to a year or more and can be very challenging. This is a rare situation for several reasons. First, nearly all manufacturers contacted use contract printers for all of their printing needs and contract printers have access to a broader selection of printing equipment that can handle folding requirements for many sizes of PIs. Second, only some SLCs result in changes to PI sizes, and not all of these require changes to folds. Third, manufacturers and printers alike indicate that they are aware when they are approaching a size limitation and plan for changes to PI size in advance.

5.3 Medication Guide Additions

MGs can be added to the PI or as a separate insert. Creation of the MG can add time to artwork, although the MG layout can be worked on simultaneously with other changes to labeling. As noted in Section 4.1, when MGs are newly added to the product, a statement has to be included on the carton and this could add time to the process because changes to multiple levels of labeling have to be managed. Although the multiple levels of labeling can be modified simultaneously, the coordination required and any potential complications due to unusual printing media could add significant time to the implementation timeline. Furthermore, due to the extra bulk of paper, in some cases, the addition of the insert can require an increase in carton size. This is discussed further below.

5.4 Carton Size Changes

When pharmaceutical inserts increase in size due to labeling changes, it sometimes no longer fits into the carton and cartons have to increase in size. This size increase in the immediate carton can also result in a need to change the size of tertiary packaging, such as shipping cartons. Additionally, the resulting increase in carton size can affect the retail shelf space required for the product, requiring manufacturers to notify retailers and distributors about this new requirement. Manufacturers estimate that this problem is encountered in about 5 to 8 percent of SLCs.

To evaluate fit, manufacturers obtain blank container, carton, and insert samples from the supplier and make handfolded samples to determine whether a new size of packaging is required. This process can add up to 3 weeks to the typical implementation timeline.

If a new size is required, the corporate labeling division will have to create experimental specifications and drawings for the new cartons, which requires an additional 3 to 4 weeks. The manufacturer will also have to order, receive and inspect test samples and schedule and conduct line validation trials (including possible packaging validation), which can take another 4 to 8 weeks. Internal change management processes and finishing the artwork can be completed in parallel. Hence, a full redesign of secondary and tertiary cartons can add up to 7 to 12 weeks to the implementation timeline. The process can be challenging to schedule and manage if other products are packaged on the same line.

In some cases, retooling of a packaging line might be needed or new packaging equipment will have to be purchased because the current packaging equipment cannot accommodate the increased package size. In one case, a manufacturer had to take the product off the automated packaging line and hire people to hand-pack product while waiting for new equipment to be ordered, installed, and qualified. Retooling requires ordering new pieces for packaging equipment, which can take up to 3 months to receive because the pieces are built to order. Validating the packaging line and completing trial runs adds another 3 weeks. Thus, the entire process of retooling a packaging line can add up to 5 to 6 months. Complete replacement of a machine would take even more time and money.

5.5 Multiple Levels and Versions of Labeling

Multiple levels (e.g., container, carton, shipping carton) and versions (different SKUs) of labeling can also complicate timelines. The average presentation of drug products is 3 types of formats (e.g., physician samples, hospital unit blister packs, bottles) but there can be as many as 7 or more. Furthermore, each format comes in different sizes (e.g., bottles of 30, 60 and 90 tablets). Unique labeling artwork and proofs are often needed for each SKU. Each SKU has a separate master packaging record that needs to reviewed and approved. Thus the greater the number of SKUs affected, the greater the workload. If container and carton labels change as well then the container label and carton proofs would require review and approval from multiple departments as well.

Although manufacturers work in parallel on all layouts, there will be more coordination and potential for errors due to the multiple versions. Thus manufacturers are more careful and do more reviews, including of the versions received from FDA after approval. This additional review can also add several weeks to the typical timeline.

5.6 Foreign Establishments

If products are manufactured abroad, this can pose additional challenges under any implementation scenario other than one in which a date is set for the SLC to appear in packaging. First of all, shipping time from these establishments can be significant and needs to be considered in any scenario that might involve repackaging of product because product would need to be sent back to the original packaging source (or repackaged by hand). Ocean transport of finished product can range from 4 to 6 weeks. Furthermore, customs clearance and quality control release can add up to 2 more weeks in the final destination. Foreign establishments also have larger inventories to allow for transport delays so these take longer to deplete than for similar products at domestic establishments. Thus, if an SLC must be in shipped product, longer lead times would be needed to prevent repackaging or drug shortages. Some foreign establishments also face longer print vendor lead times than the average seen for domestic establishments. Furthermore, in some cases, products manufactured at multiple foreign establishments might be affected. The additional coordination required for such operations can add 1 to 3 weeks to the typical labeling implementation timeline (Fontaine, 2012).

For products manufactured in the U.S. but sold internationally, labeling approval outside the U.S. might also be required. Manufacturers have to determine the specific regulations of each country and comply with them. After FDA approval, label approval by foreign agencies can take additional time before products can be exported. It is more common to have a U.S. label (i.e., when a manufacturer has registered a product in another country based on U.S. labeling and therefore must follow U.S. labeling) that goes to other countries than a country-specific label. In some cases, if they have sufficient inventory, manufacturers will hold product with new labeling within the U.S. until the new labeling is approved by all countries that the product is shipped to. For urgent SLCs, they will quarantine product being shipped abroad and release U.S. product. In such situations, they will also be in communication with FDA to

manage supply and determine the best approach. Extending the time for having SLCs in packaged product might be necessary in some cases to avoid global supply disruptions.

5.7 Integration with Other Regulatory Requirements

Manufacturers, in some cases, also have to consider other regulatory requirements, such as risk evaluation and mitigation strategies (REMS) requirement elements to assure safe use (ETASU) or class labeling changes, when making safety labeling changes. Manufacturers try to bundle multiple changes to lower printing costs and minimize disruption to the supply chain. They may hold off or accelerate implementation of a change, depending on demand. Bundling is more likely contemplated if the product is manufactured only once per year than if it is packaged monthly. Hence, if other regulatory submissions that could result in labeling changes are pending, and the change to the safety section of the labeling is minor, it can be delayed until the next labeling changes are made.

REMS requirements are routinely reassessed by manufacturers if a product is covered by REMS and may be affected by safety labeling changes. If a safety labeling change requires modification of a REMS element (e.g., health care provider and pharmacy certification forms, patient agreement forms, educational materials, prescriber, patient, and pharmacy brochures, instruction guides, and other relevant REMS materials needing prior FDA-approval), REMS documents have to be reviewed and revised by the manufacturer and FDA. Training of staff, health care providers, and patients on the new element also has to be completed (including contractors). Even in cases where a REMS element is not directly affected, labeling changes might still affect some of the REMS materials or procedures indirectly. These impacts could add significant time to implementing new labeling if the manufacturer strives to harmonize all changes. Sometimes the REMS documents and other labeling changes are approved at different times and so the PI and the MG are not harmonized for some period of time. Manufacturer H has a recent example of a case where the PI has newly approved warnings but the revised MG associated with REMS has not been approved yet. Although the manufacturer was not comfortable with this situation, it does not necessarily mean an SLC cannot be expedited under these circumstances.

5.8 Generic vs. Branded Drugs

Generic drugs have some special challenges with regard to timelines compared to branded drugs. The differences are inherent in the fact that generic drug manufacturers have the duty to exactly match nearly all of the text of brand holder’s labeling. Although manufacturers of branded drugs are aware of timelines associated with approval of labeling changes, generic drugs are dependent on when the brand manufacturer gets labeling approval. Furthermore, FDA is not required to notify the generic drug manufacturers of any changes, and there is no central repository of labeling. Thus, generic manufacturers use emails from FDA, Daily Med, Medwatch summaries, Drugs at FDA, information from drug information vendors (if they are subscribers), and manufacturer websites to learn about changes. Because the generics manufacturer is not directly informed and must research any changes, there can be a lag of as much as a month before they become aware a change has been made even with their best diligence. Thus, the timeline from FDA approval to printed labeling can be increased by as much as a month, all other things being equal.

Once generic manufacturers receive new labeling, typical implementation timelines for generics manufacturers ERG spoke with are much shorter than those of branded manufacturers. The two generic manufacturers that reported implementation timelines package immediately after they manufacture product and package frequently. Thus, they are generally able to get new labeling into the next packaging run in 30 to 60 days. One also noted that a 4- to 5-month timeline from when they identify a change to when product is shipped with new labeling is manageable for them.

6.0 LESSONS LEARNED

This section provides some key insights for how FDA might work within the typical and unusual timelines and various implementation choices to manage the process of SLC implementation. ERG has distilled the most relevant information for FDA from our conversations with manufacturers and others in the pharmaceutical supply chain, as well as from comments on questions posed by FDA in the Federal Register Notice with regard to implementation scenarios, timelines, and exceptions to those timelines. The following bullets list these considerations:

 Implementation scenarios that go beyond specifying a deadline for revised labeling to appear in packaging are likely to be time consuming and complicated for FDA if repackaging, recalls, and drug shortages are to be avoided.

o Implementation scenarios that include setting a general date for revised labeling to appear in shipments from the manufacturer or wholesaler or for revised labeling to be available to the end user for a majority of manufacturers for most SLCs are likely to be infeasible. Highly variable manufacturing cycles and inventory levels lead to a need for case-by-case deadlines for these types of implementation scenarios. For example, when FDA set a date for revised labeling to be present in shipped product, as discussed in the case study of quinolones and Case Study 2, packaging cycles and inventory became key factors in when a deadline can be met without requiring repackaging or creating shortages. When these factors became an issue for affected manufacturers, FDA worked closely with each one to establish an appropriate deadline.

o Implementation that is defined beyond the point where manufacturers have control of the product (e.g., at the wholesaler or retailer) is likely to be impractical and difficult to accomplish without triggering recalls. Wholesalers will not likely take responsibility for relabeling and even if a date is set well beyond usual inventory times, a check on stocks might still need to be made for any lingering product.

 An implementation scenario that sets general deadlines for electronic distribution and for revised labeling to be packaged with product, on the other hand, could be practical and relatively simple in most cases.

o Most manufacturers, within weeks of FDA approval of the SLC, completed the following tasks: placing revised labeling on websites, sending out Dear Healthcare Provider letters, providing FDA with SPL versions of labeling, informing drug information vendors and/or creating new materials for sales staff.

o Nearly all manufacturers under nearly all situations are able to get printed labeling ready for packaging in the next packaging run within six months of approval (assuming a run is made in that time). Many manufacturers formally or informally consider this time frame standard operating procedure, although low priority SLCs might not adhere to this timeline.

o Some manufacturers are able to get printed labeling ready for packaging within four months of receiving FDA approval. It is beneficial to have SOPs in place to handle high priority SLCs., The following caveats should be considered , however:

. That not all SLCs are considered high priority (e.g., if only FDAAA-required changes are given deadlines) so that in most cases only a few high priority changes are being managed at any one time.

. That additional time is granted for certain exceptions, including unusual printing media, PI size changes (or the requirement to convert to PLR format are suspended for a specific SLC), including MG additions, carton size changes, multiple levels of labeling and versions (numerous SKUs) and export issues.

 Most changes in PI size and MG additions can probably be done within the four month timeframe if package size changes requiring new packaging equipment or retooling are not triggered.

 Some carton size changes might be accommodated in this time frame if the packaging equipment can be adjusted to fit the new size cartons.

 The artwork time and coordination time to manage a few levels and versions of labeling can most likely be accommodated. More levels with many versions of labeling might require additional time, but 4 months should be adequate for most such cases. A 3-month deadline would most likely increase the number of manufacturers needing more time to make changes to multiple artwork files.

 Unusual printing media, export issues, and cases in which retooling or new packaging equipment is needed to handle carton size changes might still be an issue. These issues, however, are likely to occur very infrequently.

 There may be other issues that neither ERG nor FDA’s notice elicited, but such issues are also probably rare.

Appendix A: Summary of NODA Comments

QUESTION 1 - Drug Manufacturing & Packaging

What are the considerations related to drug manufacturing and packaging, of which FDA should be aware, as they relate to implementation of revised product labeling?

A.1.1. Clearly Define Implementation

Commenters contributing information on which Summary is based:  Celgene  Novo Nordisk  Pfizer  Boehringer Ingelheim

Commenters request FDA to clearly define “implementation” of new/revised labeling as when the product is first packaged with new labeling, specific points along the supply chain, or the last date the older artwork can be used in manufacturing. One commenter recommended that “implementation” be defined as the date of first packaging run (Celgene). According to the commenter, if it is defined as completion of a step further down the supply chain it can have a negative impact on product supply, resulting in product destruction potentially leading to drug shortages. Another commenter suggested that the definition of an implementation date for promotional labeling should be a date within the manufacturer’s control (e.g., to define implementation as the date after which updated labeling must be used in new promotional materials).

A.1.2. Consider Impact of Variation of Manufacturing Cycles

Commenters contributing information on which Summary is based:  Bausch & Lomb (B&L)  Baxter  Biotechnology Industry Organization (BIO)  Celgene  Novartis  Pharmaceutical Research and Manufacturers of America (PhRMA)

Commenters encouraged FDA to consider the frequency with which products are manufactured. Based on demand, expiration date, existing inventory and other considerations, some products may only be manufactured periodically (e.g., every 2 years) while other high volume products maybe manufactured daily (B&L). Demand profiles for newer products tend to be higher, leading to more manufacturing runs. Manufacturing cycles can range from every 3 months for new products to greater than every three years for older products (PhRMA). Two commenters mentioned that they do not typically schedule special production runs to implement revised labeling (BIO and PhRMA).

They caution the Agency in developing timeframes and language that might inadvertently imply that a batch must be manufactured to implement an important change (B&L). Commenters expressed that trying to fit unscheduled manufacturing runs into an already defined manufacturing schedule can be challenging (BIO).

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A.1.3. Avoid Timelines That Result in Recalls

Commenters contributing information on which Summary is based:  Gilead Sciences  Health Care Distribution Management Association (HDMA)  Pharmaceutical Printed Literature Association (PPLA)  Sanofi

Commenters encouraged the Agency to avoid timelines that result in recalls. This is because recalls cause severe disruptions in the supply chain, which can lead to drug shortages. Recalls are also financially burdensome. The seriousness of the new safety information should be considered in deciding whether a product recall is required or if a labeling revision needs to be made immediately. The decision to require a recall should be based on many factors, including the size of the population affected by the labeling change, the health risk associated with the change, and the ability to positively affect patient outcomes (PPLA). One commenter requested that FDA allow products that are already in distribution to remain in distribution until expiry. Furthermore, FDA should not require repackaging of product with a revised label if it is already in distribution (HDMA). Also, this commenter thinks that requiring the recall or relabeling of product already in distribution due to a labeling change is counter to industry and agency efforts to move to “paperless” labeling.

Additionally, one commenter notes that FDA’s drug recall website did not indicate any recall resulting from improper printed inserts (PPLA). Another commenter mentions that recalls could adversely affect patient perceptions and could increase anxiety (Gilead).

A.1.4. Impact of International Manufacturing Sites on Timelines

Commenters contributing information on which Summary is based:  Baxter  Boehringer Ingelheim  Novartis  Pfizer  PhRMA

Commenters expressed concern that it will be costly for companies with foreign manufacturing sites because they will have more inventory to deplete due to the extra inventory they maintain to allow for transport delays. Along with shipping delays, manufacturers at foreign establishments also face longer print vendor lead-times.

A.1.5. Companies Generally Do Not Schedule Special Runs to Implement Revised Labeling

Commenters contributing information on which Summary is based:  PhRMA  BIO

Two commenters mentioned that companies typically do not schedule special production runs for the purpose of implementing revised labeling (BIO and PhRMA). Although companies might try to modify the existing production schedule (e.g., delay packaging), they risk creating waste and unneeded inventory if product is manufactured without a demand for that additional production. Commenters also raised

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concern that fitting new manufacturing runs into an already defined schedule would affect scheduling of new manufacturing runs for other products.

A.1.6. FDA Should Avoid Language Indicating a Batch Must Be Run in Order to Implement the SLC

Commenters contributing information on which Summary is based:  B&L

The commenter cautions that FDA should not develop timeframes and language that inadvertently implies that a batch must be manufactured in order to implement an important change.

A.1.7. Consider Third-Party Packaging Lead Time

Commenters contributing information on which Summary is based:  PhRMA  Novartis  B&L  Celgene

The commenters noted that timelines for implementation can also be affected if the product or labeling involves manufacturing or printing by third parties. Third-party involvement might require additional coordination, or need to negotiate third party schedules and/or priorities. One commenter mentioned that application holders are usually contractually required to give contract packaging firms a minimum of 3-4 months lead time for production scheduling (Celgene).

A commenter noted that scheduling for products manufactured and/or packaged by a contract manufacturer and/or packaged by a contract manufacturer might require additional planning based on current scheduling for other companies, terms of contract, etc.

A.1.8. Consider Impact on Packaging Components and Timelines

Commenters contributing information on which Summary is based:  B&L  Baxter  BIO  Boehringer Ingelheim  Hospira  Novo Nordisk  Pfizer  Sanofi  Novartis  PhRMA

Addition of new, large amount of text to a PI may result in a new layout/fold that might require the manufacturer to assess current equipment to accommodate a larger PI. A change in PI specification can affect the carton size (e.g. larger carton, new seal location). They will have to perform line trials to assess current equipment capabilities, which might require them to either retool current equipment or buy new equipment. Furthermore, line trials must be scheduled such that there are minimum disruptions to supply

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of other important drugs. Manufacturing validation due to change in overall size of the PI (i.e. conversion to PLR format) will take around 3 weeks (Hospira). Similarly, design changes to secondary or tertiary packaging due to a change in overall size of PI could take another 3 weeks. All the above processes will add several weeks to months of lead time for label implementation.

Temporary manual packaging options could be used but there are concerns with costs and pressure to maintain supply.

A.1.9. FDA Should Define Expected Company Response Whether Electronically, in Packaging, or in Shipments)

Commenters contributing information on which Summary is based:  Sanofi

The commenter requested FDA to list expected company responses and reactions. They suggested that a draft of the notification and direction could be developed jointly between the FDA and the company prior to issuing, taking into consideration all the variables so at the time the update is issued the company can react correctly and more timely.

QUESTION 2 - PRINTED LABELS AND OTHER TYPES OF LABELING

What are the considerations related to printed labels and other types of labeling of which FDA should be aware, as they relate to implementation of different types of revised product labeling?

A.2.1. Account for Lead Time to Get Artwork Done

Commenters contributing information on which Summary is based:  BIO  Novo Nordisk  Celgene  Hospira  PhRMA  Sanofi

Upon receipt of FDA approval, manufacturers will have to prepare artwork, which in most cases will include having a third-party printer type set the new label text (Celgene). The creation of the artwork will then be followed with a series of reviews and approval by multiple departments. Once the typeset is approved, a third party will prepare the “printer proof,” which is again reviewed and approved and then sent for printing. Composing artwork for each style and format of packaging takes about 1 to 21 days (Hospira, PhRMA). It takes 1 to 14 days to route composed artwork for internal review and approximately 1 to 7 days to prepare artwork for release, resulting in a total lead time of 3 days to 6 weeks. Various layouts might be needed to support the variety of package presentations marketed (e.g. different sheet sizes and folds for bottles used at pharmacies vs. blister packs used for hospital presentations. Another commenter mentioned that labeling changes usually impact multiple strengths of a particular product thereby multiplying the lead time (Celgene). Due to the many activities involved in the process, the commenters requested sufficient lead time to initiate artwork, conduct quality reviews, and print labeling for packaging.

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A.2.2. Account for Lead Time for Printing

Commenters contributing information on which Summary is based:  PPLA  Novartis  Sanofi  PhRMA  Hospira  Torrent  Pfizer

Current packaging suppliers of printed labeling demonstrate repeat capability to produce defect-free printed packaging within 8-24 hours of receiving approved copy (PPLA). For some formulations, and for some packaging types (i.e. on-line printing for ampoules or vials), the lead timelines can be extensive. If a revised labeling affects an immediate container, this may further extend lead times; e.g., printed tubes have a lead-time of 16 weeks, as does the production of gravure cylinders used for printing of flexible packaging material such as, blister foil or pouches (PhRMA). One commenter mentioned that the revision to foil imprint plates used in flexible container packaging requires a minimum of 8 weeks of lead-time (Hospira). Commenters indicated that printing can be expedited but this requires a high level of coordination among different parties and is done at a very high cost.

A.2.3. Multiple Labeling Changes with Overlapping Time Frames Can Increase Implementation Times

Commenters contributing information on which Summary is based:  Novartis  PhRMA

Multiple labeling changes might have been submitted to FDA over a period of time, and not all outstanding changes are approved by the FDA simultaneously. Therefore, it is possible that there may be multiple labeling changes approved in a timeframe that would result in potentially overlapping timeframes for implementation in various formats, which needs to be considered (Novartis). In such circumstances manufacturers try to bundle these changes into a single update to ensure the least disruption to the supply chain and also to decrease costs associated with printing (PhRMA). Commenters expressed that it is most efficient if the label changes are approved simultaneously.

A.2.4. Various Layouts Needed for Multiple SKUs Affected By the Same SLC Increase Timelines

Commenters contributing information on which Summary is based:  PhRMA

The commenter explained that various layouts may be needed to support the variety of package presentations marketed (e.g. different sheet sizes and folds for bottles used at pharmacies vs. blister packs used for hospital presentations).

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A.2.5. Electronic Labeling is Fastest to Implement and Promotional Labeling Can Be Implemented Faster than Printed Prescribing and Patient Labeling

Commenters contributing information on which Summary is based:  B&L  Baxter  BIO  Boehringer Ingelheim  Celgene  Gilead  HDMA  Hospira  John D. Hill  National Association of Chain Drug Stores (NACDS)  Novartis  Novo Nordisk  Pfizer  PPLA  PhRMA  Sanofi  Torrent

With the exception of one commenter (PPLA), all commenters preferred electronic labeling to printed paper labeling and supported the move toward “paperless labeling.” They believed that communicating the updated safety information is the fastest and the most efficient way to disseminate information to healthcare professionals as well as to patients. Many commenters commended the agency’s effort to move toward “paperless labeling.” On the other hand, one commenter argued that while the use of electronic medium for critical labeling information should be considered and developed, it should not be a substitute for printed labeling that accompanies the drug product. According to this commenter, electronic medium has the inherent risk of service disruption, system failure, and lack of accessibility by all patient consumer or healthcare professionals. The commenter further noted that the current distribution of printed information provides the most cost-effective way to ensure the presence of all required information and is the quickest point of reference for medical professionals in any situation (PPLA).

A.2.6. Color Requirements Could Involve Additional Time for Ink Qualification

Commenters contributing information on which Summary is based:  Baxter

One commenter stated labeling formatting issue related to color limitations due to ink qualification.

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QUESTION 3 - SUPPLY CHAIN FACTORS

What are the supply chain factors (including storage, shipping, and distribution factors) of which FDA should be aware that limit or otherwise affect how quickly a labeling change can be implemented?

A.3.1. FDA Should Not Require Revised PIs for Drugs Already in Distribution

Commenters contributing information on which Summary is based:  Baxter  Pfizer  HDMA

Commenters supported the perspective that those products that have moved beyond the manufacturing line should not be withdrawn from distribution to implement changes to existing labeling. One commenter explained that once a product is shipped by manufacturer through the supply chain, it is not readily accessible to the manufacturer for implementation of a quick labeling change (Pfizer). Because recall of the products already in distribution is highly burdensome, costly and disruptive, a commenter requested FDA to allow products already in distribution to remain in distribution until expiry and that the agency should not require the revised PI to be affixed to products already in distribution (HDMA). If that is not possible, they urged FDA to allow at least six months beyond a deadline for manufacturers for wholesale distributors to complete the changeover to the revised PPI. They noted that the additional time is necessary to ensure smooth transition.

A.3.2. Consider Batch Release Timeframes

Commenters contributing information on which Summary is based:  Baxter

The timing for conducting certain release testing (i.e. sterility tests) should be considered in the overall timeframe established for implementing a labeling change because it affects the overall manufacturing timeline.

A.3.3. Timeframe to Avoid Shortage Must Consider Stock Rotation and Inventory for Safety Stock

Commenters contributing information on which Summary is based:  Boehringer Ingelheim  Celgene  Novartis  HDMA  PhRMA  Sanofi  Novo Nordisk

In an effort to avoid drug shortages, pharmaceutical companies hold safety stock in their inventories. For some products, the amount of safety stock is equivalent to several months of product sales. If FDA defined implementation as shipment by the application holder to wholesale customers, a requirement to implement labeling within a pre-specified time period (e.g., 3 to 6 months) could result in destruction of

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inventory of product packaged with the prior labeling version. This could lead to a shortage or immediate stock out of a critical drug product (Celgene, Sanofi). Even though safety stocks are critical to operations and prevention of drug shortages, the challenge comes when rework of existing stock in their warehouse(s) is necessary and limits quick implementation of safety labeling changes (Boehringer Ingelheim).

One commenter mentioned that in their experience, many dispensers, including retail pharmacies and hospitals, have stock rotation practices that involve returning product that is within six months of its expiration to the manufacturer (HDMA). For some products that need to be temperature controlled, additional relabeling/repackaging can put the material at risk, again creating risks to product supply (PhRMA). Commenters believe that mandating defined timelines for implementing revised labeling in product packaging should be minimized because they would adversely affect continuous drug supply.

A.3.4. Must Define Distribution More Clearly

Commenters contributing information on which Summary is based:  Boehringer Ingelheim

The commenter requested clarity regarding the term “distribution.” In the FR “SUPPLEMENTARY INFORMATION: I. Background,” the last sentence in second paragraph “Typically products that had already been moved beyond the manufacturing line…” – The commenter stated that the definition of “distribution” needs clarification (e.g., whether it includes shared warehouses with other companies)

A.3.5. Can Encounter QC Bottlenecks

Commenters contributing information on which Summary is based:  PhRMA  Novartis

Once product is packaged, it is released for sale by Quality Control (QC) and is generally shipped to company warehouses. A potential bottleneck in the release by QC might occur due to quality investigation/deviations related to the batch (PhRMA, Novartis). A final QC release from the sponsor can take 1 to 14 days as estimated by one commenter (PhRMA).

A.3.6. Overseas Transport Times and Customs Clearances Can Delay Implementation in Supply Chain

Commenters contributing information on which Summary is based:  PhRMA  Novartis  Boehringer  Torrent

Products that are manufactured and packaged outside of the US for distribution in the U.S. face longer shipping times (Boehringer, Torrent) than domestically manufactured products. The mode of transportation (e.g., ocean transport of finished goods packaged in Europe to the U.S.) is approximately four weeks and for goods packaged in Asia, six weeks. These shipping times might affect how quickly product can reach a warehouse (PhRMA). Also, there is time associated with Customs clearance and QC release at the final destination, which might take up to two weeks (Novartis, PhRMA).

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A.3.7. Lower Volume Products Result in Higher Inventory Levels

Commenters contributing information on which Summary is based:  Baxter  Hospira

On average, the manufacturing facility, distribution channels, and customer inventory typically carry higher inventory levels for lower volume products and as such could affect the timing for the updated labeling to be available to the public (Baxter).

A.3.8. Give Option to Deplete Inventory First; Implementation in Supply is Challenging and Can Affect Supply

Commenters contributing information on which Summary is based:  Celgene  Pfizer  PhRMA  BIO

In an effort to avoid drug shortages, pharmaceutical companies keep safety stock in their inventories. Six months of inventory on hand was mentioned as a realistic target companies strive for (BIO). For some products, the amount of safety stock is equivalent to several months of sales of products (Celgene). Another commenter estimated an average of 8 to 12 weeks of product inventory at their warehouse (Pfizer). However, it was noted that the average represents a broad range of inventory varying from as little as 7 weeks to as much as 1 to 3 years. Product containing new labeling would be used to fulfill customer orders only when existing inventory of product containing an older version of the labeling has been depleted (Celgene). One commenter agreed with the FDA’s comment that “in most cases, as in the past, it will not be necessary for products with existing labeling to be withdrawn from distribution and that under certain circumstances it may be appropriate for products with existing labeling to remain in distribution until the current product inventory is exhausted.,” The commenter also believed that this should be the norm (PhRMA). Using up existing inventory also minimizes waste and saves cost (BIO).

A.3.9. Repackaging Can Cause Supply Disruptions

Commenters contributing information on which Summary is based:  Bio  PhRMA

Commenters raised concern that repackaging to comply with a mandated implementation for printer materials can disrupt manufacturing/supply of the product in question as well as other products associated with the same packaging line (BIO, PhRMA).

A.3.10. Wholesalers Hold for 2.5 to 6 Weeks

Commenters contributing information on which Summary is based:  Pfizer

The commenter indicated that wholesalers typically hold 2.5 to 6 weeks of inventory.

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A.3.11. Retail Holds 2.5 Weeks of Inventory

Commenters contributing information on which Summary is based:  Pfizer

Commenter approximated a 2.5 weeks of inventory at retail pharmacies, although they might stockpile certain items.

A.3.12. Hospitals Hold 5 to 8 Weeks of Inventory

Commenters contributing information on which Summary is based:  Pfizer

Commenter indicated that hospitals typically carry more inventory, with lower turnover. The average turnover was estimated at 5 to 8 weeks. It was noted that these numbers are best case scenario and do not factor in situations where they might stockpile certain items for any number of reasons or where a particular product is only used rarely.

QUESTION 4 - Alternative Labeling Mechanisms

What alternative labeling mechanisms (e.g., having labeling available on a product Web site) could be used to disseminate new safety information quickly to patients and health care providers?

A.4.1. Suggestions for Alternatives

Commenters contributing information on which Summary is based:  Bausch & Lomb  Baxter  BIO  Celgene  Hospira  John D. Hill  NACDS  Novartis  Novo Nordisk  Pfizer  PPLA  PhRMA  Sanofi  Torrent

Almost all of the commenters encouraged the use of alternative mechanisms by manufacturers to communicate new information quickly. They included “Dear Healthcare Provider” letters and emails and publication of updated labeling on-line, both on company-sponsored websites and SPL on National Library of Medicine/DailyMed. Commenters also mentioned medical conferences, social media, FDA announcements/postings, and RSS feeds from the Agency. Some suggested that company representatives (sales representative or Medical Science Liaisons) can also be deployed to advise healthcare professionals of updated labels even before printed labeling has been finalized. Other suggestions include an electronic

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compendium such as that found in the UK, QR codes for smartphones (barcode reading applications), the formal establishment of DailyMed as the primary authoritative source for drug information, requirements that revised labeling be posted on product websites within 10 days (although some manufacturers do not have product websites), and pharmacy printouts based on database (one commenter disagrees with pharmacy printouts due to shift of risk from manufacturer to pharmacy and because of state regulation of pharmacies[PPLA]). One commenter suggested harmonizing existing product labeling such as patient PIs and MGs, along with other written information targeted to patients, into a single patient medication information (PMI) document that is standardized with respect to format and content (the “one-document solution”) (NACDS)

A.4.2. PPLA Prefers Printed Labeling

Commenters contributing information on which Summary is based:  PPLA

According to the commenter, although use of electronic medium for critical labeling information should be considered and developed, it should not be used as a substitute for printed labeling that accompanies the drug product. They believe that electronic media, although also invaluable, have the inherent risk of service disruption, system failure, and lack of accessibility by all patient consumers or healthcare professionals. For example various distribution markets, military deployment, rural, and lower-income households, might not be able to access electronic information. While allowing for and enhancing electronic communication of labeling changes, rapid deployment of revised printed labeling should also continue to be required. They think that although electronic resources serve as complementary warning systems for safety labeling changes, the current distribution of printed information provides the most cost- effective way to ensure the presence of all required information and is the quickest point of reference for medical professionals in any situation. Hence, they suggest FDA encourage manufacturers to use multiple channels of communication for labeling changes, but should continue to require that product labeling accompany the drug product.

QUESTION 5 - Risk Assessment

How should the relative seriousness of the new safety information, or whether the new safety information describes a newly identified risk, or strengthens a risk already identified in current labeling, affect timelines for implementing revised product labeling?

A.5.1. Switch to Electronic Labeling for Serious Risks to Avoid Tiered Approach

Commenters contributing information on which Summary is based:  Novo Nordisk

Distribution of important safety information through electronic means will always be communicated quickly and more efficiently than through printed labeling. Developing a tiered approach to seriousness becomes irrelevant when electronic dissemination is used because the information is distributed very quickly through electronic means.

A.5.2. Tiered Approach Should Be Based on Relative Severity

Commenters contributing information on which Summary is based:  Novo Nordisk

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 Torrent  Boehringer Ingelheim  PPLA  B&L  Pfizer

Commenters believed that the relative seriousness of new safety information should be considered when establishing implementation plans (Novo Nordisk, Boehringer Inglelheim). The decision should be based on many factors, including of the size of the population effected by the labeling change, the health risk associated with the change, and the ability to more positively affect patient outcomes (PPLA). Another commenter acknowledged that labeling revisions due to a newly identified risk, particularly a new or strengthened boxed warning, new serious adverse drug reaction, or new contraindication should follow an expeditious implementation timeline. If a risk already identified in current labeling is strengthened from a precaution to a warning (rather than a case in which the risk is strengthened for clarification but remains a precaution) it might be appropriate to set a flexible, adaptive implementation period to incorporate the revision into the label (B&L).

With regards to implementing safety updates in promotional labeling, one commenter encouraged FDA to allow manufactures to address timing on a case-by-case basis, subject to the seriousness of the labeling change, including whether it describes a new risk or strengthens a risk already in the labeling, as well as the general risk-benefit profile of the product involved (Pfizer). One commenter suggested a 3 month implementation timeframe in-packaging for more serious safety changes and 6 months implementation for less serious safety changes from the date of approval (Torrent).

A.5.3. Paperless labeling obviates need to identify risk level; all SLCs can be implemented swiftly through this route

QUESTION 6 - Reasonable timeframe

What would be a reasonable timeframe following approval of revised safety related labeling changes for applicants to implement the revised labeling? Please relate this timeframe to the optimal point in the supply chain (e.g., newly manufactured product, newly shipped product) and the type of labeling change.

A.6.1. No Timeline, Case-by-Case Timelines, or Timeline to Be Set by Manufacturer

Commenters contributing information on which Summary is based:  BIO  Celgene  John D. Hill  Novartis  Pfizer

Some commenters do not believe that it is appropriate to establish fixed, inflexible timeframes to govern the implementation of paper label revisions due all the complexities involved in planning and production (BIO, Novartis). Others think that each labeling change is a unique situation with unique circumstances that should be taken into account when establishing timelines for implementing revised product labeling. They believe that what may be reasonable in one situation may not be appropriate for another. Thus, they suggest that any FDA guidance on this matter should recommend that the applicable FDA Division work

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with the application holder to establish a “reasonable” time period for label implementation or use a case- by-case approach to implement safety labeling changes (Celgene, Pfizer). According to one commenter, manufacturers should be allowed to schedule reasonable implementation timeframes so as to mitigate risk of supply disruptions due to mandatory package labeling changes (John D. Hill).

A.6.2. Different Timelines Should Be Set for Electronic, Promotional and Paper Labeling

Commenters contributing information on which Summary is based:  Baxter  BIO  Gilead  Novartis  PhRMA  Sanofi  Torrent  Celgene

Commenters suggested that FDA should consider appropriate timelines for implementing safety labeling changes in different forms. Most commenters thought that it was reasonable for the Sponsor to post the revised label on their website as soon as practicable, or within 10 days. Sponsors can provide a copy of the Structure Product Labeling (SPL) to FDA within 14 days, which then gets forwarded to NLM, which updates DailyMed with the revised label within 24 hours of receipt from FDA.

A commenter discussed that product labeling accompanying promotion can be printed and available for distribution within several weeks. However, if the safety labeling changes warrant revision of the promotional materials themselves, implementation timelines may vary depending on the nature of the materials. Some types of promotional materials, such as printed sales aids, can be revised, reviewed, can produced more quickly than others. Those with longer lead times include videos, print advertisements in journals and magazines, etc (Novartis). According to one commenter, safety label changes cannot be implemented in promotional materials for Subpart H products until the end of the pre-clearance period (30 days), at which time the material can be sent for final printing (Celgene).

Commenters indicated that labeling associated with product packaging requires the greatest lead times. In the case of paper labeling in packaging, commenters believed that 6 months for printed labeling to be in packaging is reasonable. Provided no equipment/technology changes are required, they estimated a timeframe of 6 months to implement into next batch production for high risk, significant safety updates, and 9 months for low risk safety updates (Baxter). One commenter mentioned that it would take 3 to 6 months to implement at the consumer level with possible stock outs during that time (Sanofi). Another commenter suggested 3 months for more serious safety changes and 6 months for less serious safety changes to be implemented from the date of approval (Torrent).

A.6.3. FDA Should Transition to Paperless Labeling

Commenters contributing information on which Summary is based:  Pfizer  Celgene  Novartis  PhRMA

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Many commenters believe that paperless labeling would be a more effective and efficient way to ensure that updated labeling is available to patients and health care providers in a timely manner. According to them, paperless labeling is the best option for finished, packaged drugs products e.g. websites, bar codes, serial number, smart phone and pedigree on drug packaging (Pfizer, Novartis, PhRMA). According to one commenter, it could be beneficial to eliminate printing labeling because outdated printed labeling is always present in the distribution channel, thereby creating confusion. If labeling becomes paperless, implementation of printed labeling would be moot (Celgene). Paperless labeling does not have the special challenges of paper labeling; it is easier to read, and has the most up to date information (PhRMA).

A.6.4. Implementation Should Imply “In Packaging” To Be Least Disruptive of Drug Supply

Commenters contributing information on which Summary is based:  Celgene  Novo Nordisk  Gilead  Pfizer  Torrent

Some commenters stress that “implementation” by the manufacturer in packaging should mean the date that the product is first packaged with the new labeling (i.e., the date of the first packaging run), not the date a package containing the new label is first introduced into interstate commerce. If it is defined as a completion of a step further downstream in the process, it could result in a negative impact on the supply of product, potentially leading to drug shortages (Celgene). One commenter mentioned that once a product is shipped by a manufacturer through the pharmaceutical supply chain, it is not readily accessible to the manufacturer for implementation of a quick labeling change. Hence, it might be harder to implement safety labeling changes once it is beyond manufacturer’s control (Pfizer).

A.6.5. CBEs and Some Prior Approval Supplements Should Have No Required Timelines

Commenters contributing information on which Summary is based:  BIO  B&L  Hospira  Novo Nordisk  PhRMA

According to a commenter, for those changes initiated by the Sponsor such as Changes Being Effected (CBE) Supplements and some Prior Approval Supplements there are no mandatory timeframes for review and/or action by the Agency. In such case, there should be no required implementation timelines (BIO). Another commenter recommended that the Agency should reserve the existing procedures (e.g. Prior Approval Supplement, etc.) for less serious safety updates (Novo Nordisk). One commenter requests FDA to apply timelines only to those changes mandated by FDA based on new safety information under section 504(o)(4) of the Federal Food, Drug and Cosmetic Act (PhRMA).

A.6.6. FDA Should Not Mandate Timelines

Commenters contributing information on which Summary is based:  Novartis

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 Celgene  PhRMA

Some commenters believe that there is no compelling reason for the FDA to impose mandatory timeframes for the implementation of labeling changes in printed packaging. Doing so may result in unintended consequences such as stock outs for the product due to destruction of inventory or for other products whose manufacture might need to be postponed due to the potential need for reprioritization of labeling changes (PhRMA, Celgene). Hence, mandating defined timelines for implementing product packaging should be minimized (Novartis).

A.6.7. Consider Alternate Means of Communication for Products Administered in Controlled Settings

Commenters contributing information on which Summary is based:  Baxter

The commenter requested that special considerations should be given to those products such as parenteral drug products administered by a healthcare practitioner in a controlled setting (such as hospital). Utilization of alternate means of communication is more practical when targeted at the healthcare practitioner.

A.6.8. Recalls Can Cause Drug Shortages and Other Problems

Commenters contributing information on which Summary is based:  HDMA  Sanofi  Gilead

Commenters believe that requiring recall of products already in distribution due to a change in the PPI accompanying the product would be highly burdensome, costly and result in immediate stock out of product (HDMA, Sanofi). Furthermore, they think that in recall scenarios, patient perceptions could be adversely affected and there could be increased anxiety (Gilead).

A.6.9. Certain Conditions Increase Timelines

Commenters contributing information on which Summary is based:  PhRMA  Hospira  B&L  Baxter  BIO  Boehringer Ingelheim  Novo Nordisk  Pfizer  Sanofi  Novartis

Addition of new, large amounts of text to a PI may result in a new layout/fold, which may require the manufacturer to assess current equipment to accommodate the larger PI. Change in PI specification can

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affect the carton size (e.g. larger carton, new seal location). They will have to perform line trials to assess current equipment capabilities, which may require them to either retool current equipment or buy new equipment. Furthermore, line trials should be scheduled such that there are minimum disruptions to supply of other important drugs. Manufacturing validation due to change in overall size of PI (i.e. conversion to PLR format) will take around 3 weeks (Hospira). Similarly, design change to secondary or tertiary packaging due to a change in overall size of PI could take another 3 weeks. All the above processes will add several weeks to months of lead time for label implementation.

For some formulations, and for some packaging types (i.e., on-line printing for ampoules or vials), the lead timelines can be extensive. If revised labeling affects an immediate container, this may further extend lead times; e.g., printed tubes have a lead-time of 16 weeks, as does the production of gravure cylinders used for printing of flexible packaging material such as blister foil or pouches (PhRMA). One commenter mentioned that the revision to foil imprint plates used in flexible container packaging requires a minimum of 8 weeks of lead-time (Hospira).

A.6.10. Months or Years Can Pass before Updated Labeling is Available to the Consumer

Commenters contributing information on which Summary is based:  PhRMA

The commenter noted that considering all the realities and dynamics, it may be months if not years before updated labeling is available with finished product. For printed labeling attached to product, it is estimated that a labeling change with no impact on size/format of the packaging component will generally reach the market anywhere between 3 and 30 months or more (with the difference generally being driven by product demand profiles), while a change that does not have an impact on size/format may take anywhere between 5 and 39 months or more (again the difference is driven by product demand profiles).

QUESTION 7 - Other considerations

Are there other considerations or options related to implementing safety labeling changes of which FDA should be aware?

A.7.1. Impact of Serialization

Commenters contributing information on which Summary is based:  Boehringer Ingelheim

The impact of serialization and how proposed 2D identifiers will link to product information including version control, etc. should be considered.

A.7.2. Coordination with REMS goals

Commenters contributing information on which Summary is based:  Celgene

According to the commenter, products with risk evaluation and mitigation strategies (REMS) elements to assure safe use (ETASU) pose particular challenges when implementing a safety labeling change, especially if related to the REMS goals. For safety labeling changes directly related to the REMS goals,

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there may be fundamental changes in REMS proposed and supporting documents including all REMS materials such health care provider and pharmacy certification forms, patient agreement forms, educational materials, prescriber, patient, and pharmacy brochures, instruction guides, and other relevant REMS materials needing prior FDA-approval. REMS assessment programs may need to be also changed, new proposed REMS and REMS supporting documents may need to be submitted and approved among many other things. Given this necessary cascade of events, the commenter requests FDA to avoid circumstance where changes to labeling directly affecting a REMS goal is approved but not synchronous with a REMS change. They strongly recommend that in case such a situation arises, FDA and the sponsor work closely throughout the period of evaluating such risks.

With regard to safety labeling changes not directly affecting a REMS goal, the commenter believes these change may still affect the REMS or REMS materials. Revised materials may necessitate revised training protocols both to the medical community and internal company staff. While this type of change may have relatively less impact on the REMS, there will still need to be coordination between FDA and the sponsor.

A.7.3. Difficulty of Predicting Drug Shortages/Impact of Destroying or Repackaging Product

Commenters contributing information on which Summary is based:  HDMA  Novartis  Novo Nordisk

Commenters believe that taking drugs out of the drug distribution system (by recalling, destroying or repackaging products) because of an old PPI might have the unintended consequence of limited patient access to product, especially since drug shortages are often difficult to predict or determine duration.

A.7.4. Temperature Controlled and Controlled Substances Pose Additional Challenges

Commenters contributing information on which Summary is based:  PhRMA  Sanofi

Commenters were concerned that there are additional complexities for controlled temperature and controlled substances that must be considered by the manufacturer prior to repackaging. In the instance of cold chain products, relabeling can present a logistical challenge to the time out of refrigeration (TOR). For some products, TOR may not take into consideration multiple packaging activities, and therefore the additional relabel/repack operation can put this material at risk, creating risks to product supply.

A.7.5. Keeping Product Labeling and Promotional Materials in Sync Provides Additional Challenges

Commenters contributing information on which Summary is based:  Novartis  Pfizer  Celgene  PhRMA

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Commenters noted that timeframes differ for implementation of electronic labeling, labeling associated with promotional materials, and labeling for product packaging, with electronic implementation having the fastest timeline. According to them, printed labeling, implementation planning must address not only printing of labeling itself, but also address promotional material production and release. One commenter mentioned that in addition to electronic implementation, two additional sets of Master Labeling documents must be created to support preparation of product package printing and printing associated with promotional materials (Novartis). Each format has its own timelines required for planning, preparation, quality check, production, packaging and distribution. Revision and issuance of advertising and promotional material involve multiple company processes, engagement of different vendors, and FDA submission requirements, all of which affect their implementation timeline (Celgene). Updated advertising and promotional materials can be implemented only upon submission of Form 2253 to FDA. On the other hand, for products under 21 CFR 314, Subpart H, there is an additional requirement where changes cannot be implemented in promotional material until the end of the pre-clearance period, after which the material can be sent for final printing and submitted to FDA on form 2253 (Celgene). Depending upon when in the product’s lifecycle the change occurs, a significant amount of promotional materials may be affected, thereby providing additional challenges to keep the labels in sync (PhRMA). It was mentioned that some types of promotional materials, such as printed sales aids, can be revised, reviewed, and produced more quickly than others. Those with longer lead times include videos, print advertisements in journals and magazines, etc (Novartis).

One commenter encouraged FDA to continue to allow manufacturers to address safety updates in promotional labeling on a case-by-case basis (Pfizer). They also mentioned that any definition of an implementation date for promotional labeling should be a date within the manufacturer’s control (e.g., to define implementation as the date after which updated labeling must be used in new promotional materials).

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Appendix B: References

Contract Packager A. 2012. Telephone conversation between senior level staff, Contract Packager A and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. January 2.

Contract Packager B. 2012. Telephone conversation between senior level staff, Contract Packager B and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. February 16.

Distributor A. 2012. Telephone conversation between senior level staff, Distributor A and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. February 7.

Distributor B. 2012. Telephone conversation between Distributor B and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. January 12.

Distributor C. 2012. Telephone conversation between senior level staff, Distributor C and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. February 8.

Distributor D. 2012. Telephone conversation senior level staff, Distributor D and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. January 17.

Fontaine, Leander. 2011. Telephone conversation between Leander Fontaine, President, Pharmiceutics, Inc. and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. December 19.

Fontaine, Leander. 2012. Telephone conversation between Leander Fontaine, President, Pharmiceutics, Inc. and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. January 30 and March 22.

Information Database Information Vendor A. 2012. Telephone conversation between senior level staff, Database Information Vendor A and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. March 14.

Information Database Information Vendor B. Telephone conversation between senior level staff, Database Information Vendor B and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. December 13.

Information Database Vendor C. 2011. Telephone conversation senior level staff, Information Database Vendor C and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. December 15.

Kusiak. 2011. Telephone conversation between Vicki Kusiak, MD, Supervising Medical Officer of FDA and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. November 7.

Manufacturer A. 2012. Emails to senior level staff, Manufacturer A and Ayesha Berlind and Carlie McCullough, ERG.

Manufacturer B. 2012. Telephone conversation between senior level staff, Manufacturer B and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. February 9.

Manufacturer C. 2012. Telephone conversation between senior level staff, Manufacturer C and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. February 13.

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Manufacturer D. 2012. Telephone conversation between senior level staff, Manufacturer D and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. January 4 and 31.

Manufacturer E. 2012. Correspondence between senior level staff, Manufacturer E and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. February 16.

Manufacturer F. 2011. Telephone conversation between senior level staff, Manufacturer F and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. January 25.

Manufacturer G. 2012. Telephone conversation between senior level staff, Manufacturer G and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. March 21.

Manufacturer H. 2012. Telephone conversation between senior level staff, Manufacturer H and Ayesha Berlind and Anita Singh of ERG. March 16.

Manufacturer I. 2011. Telephone conversation between senior level staff, Manufacturer I and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. December 14.

Manufacturer J. 2012. Telephone conversation between senior level staff, Manufacturer J and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. March 26, April 9 and April 13.

Manufacturer K. 2012. Telephone conversation senior level staff, Manufacturer K and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. March 20.

Manufacturer L. 2012. Telephone conversation between senior level staff, Manufacturer L and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. March 16.

Manufacturer M. 2012. Telephone conversation between senior level staff, Manufacturer M and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. February 2.

Manufacturer N. 2011. Telephone conversation between senior level staff, Manufacturer N and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. December 12.

Manufacturer N. 2012. Telephone conversation between senior level staff, Manufacturer N and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. April 25.

Manufacturer O. 2012. Telephone conversation between senior level staff, Manufacturer O and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. March 15.

Pharmaceutical Printer A. 2011. Telephone conversation between senior level staff, Printer A and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. December 12.

Pharmaceutical Printer B. 2011. Telephone conversation between senior level staff, Pharmaceutical Printer B and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. January 26.

Pharmaceutical Printer C. 2011. Telephone conversation between senior level staff, Pharmaceutical Printer C and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. December 5.

Pharmaceutical Printer D. 2011. Telephone conversation between senior level staff, Pharmaceutical Printer D, and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. December 16.

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Pharmacy A. 2012. Telephone conversation between senior level staff, Pharmacy A and Anne Jones, Ayesha Berlind, and Anita Singh of ERG. February 2.

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Appendix C: PhRMA Implementation Flowchart

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