director of Scientific Writing and Regulatory Affairs at Sciformix Corporation

Bindu Narang

	The highly debated FDA generic-drug labeling rule, which was due to be passed in July 2016, has been further delayed and is now expected to be finalized in early 2017 (1). The ruling, first unveiled in 2013, has received significant criticism from many healthcare stakeholders, with trade groups for generic-drug manufacturers continuing to fight any finalization of the ruling (2).

	Currently, generic-drug labels have to be identical to the innovator reference listed drug (RLD) label. It is the branded manufacturers (RLDs) who are responsible for updating labels with new safety information and the accuracy and adequacy of the information on these labels. The proposed rule would change that-generic-drug companies would be responsible for updating their labels, based on their own pharmacovigilance activities whenever new safety information is detected.

	One concern is that the rule could potentially cause confusion for physicians prescribing generic drugs, as multiple manufacturers updating labels separately could create different and possibly conflicting safety information. The US Congress, however, wants the final version of the rule to state that FDA must pre-approve any changes to the safety information in the labeling of a drug and an identical change be made by the RLD (3). This stipulation would require the proposed rule to be rewritten, creating the possibility that the bill may be completely abandoned (2).


	As the generic-drug label needs to be identical to the RLD, largely generic-drug manufacturers are immune to liability in failure-to-warn cases as can be seen in the 

 ruling (2). They do not have to engage in rigorous safety tracking, unlike the innovator pharma companies. Under the new ruling, generic-drug manufacturers would have to track any new safety information and update their labels by filing a CBE-0, instead of remaining identical to the RLD. Therefore, they could be held accountable in failure-to-warn cases.


	If the proposed rule goes ahead, generic-drug companies will have to strengthen their pharmacovigilance operations-from assessing safety signals to ensuring label compliance. If the rule is passed, generic-drug companies will need documented processes for safety tracking and updating labels.  For innovator companies, drug labeling is a complex and collaborative process combining multiple sources into a label. In addition to this, the local labeling information for different geographic locations is created from a global core data sheet. The complexity increases when the local labeling documents are in differing languages with different content. The labeling development process is resource-intensive, requiring input from regulatory, safety, legal, clinical, manufacturing, and other teams.

	A streamlined safety and labeling workflow would help generic-drug companies to cope with the extra safety tracking. A possible solution would be to outsource the end-to-end labeling process, which includes document management, version control, and standardization of the labeling process.

		Office of Information and Regulatory affairs, “Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products“ 

www.reginfo.gov/public/do/eAgendaViewRule?pubId=201604&RIN=0910-AG94

		Epstein Becker Green, “FDA Rule Providing Generic Manufacturers with the Ability to Unilaterally Update Safety Labels May be Abandoned” 

www.lexology.com/library/detail.aspx?g=6e97e27d-0ec7-4077-b274-a1e192ecb562

		Zachary Brennan “Updated: Congress Looks to Force FDA Into Rewriting Major Generic Drug Labeling” 

http://raps.org/Regulatory-Focus/News/2016/04/13/24750/Updated-Congress-Looks-to-Force-FDA-Into-Rewriting-Major-Generic-Drug-Labeling-Rule/

	Bindu Narang is director of Scientific Writing and Regulatory Affairs at Sciformix Corporation, 

Articles

If FDA’s proposed generic-drug labeling rule is passed in 2017, generic drug companies would need documented processes for safety tracking and label updates.

FDA’s Proposed Generic-Drug Labeling Rule: Ensuring Efficiency and Compliance

FDA proposed a new rule in December 2014 to amend its prescription drug and biological product labeling regulations. The rule applies to the electronic distribution of package inserts (PIs), which are currently provided in paper form with drug packaging for the benefit of healthcare professionals (HCPs) and consumers. The PI contains the latest information about the approved uses of the prescription drug or biological product, as well as information necessary for the safe and effective use of the product. When biopharmaceutical companies market their products in the United States, they will be required to provide the PI in an electronic file and will no longer be allowed to distribute it in paper form with the packages. FDA has proposed an effective date of six months after the publication date of the final rule in the 

 and a compliance date of two years after the date of publication of the final rule to give manufacturers time to comply (1).

	Organizations will need to find a way to fit the proposed change into their strategic labeling initiatives aimed at improving operational efficiencies and profitability, while reducing complex and disjointed processes. As the rule will be applicable only in the US, other regulated and emerging markets will still have paper-based PIs as standard practice.

	As other regulatory agencies continue to implement an evolving set of rules regarding the format and presentation of the package insert, companies will now have a double challenge. In the short term, they need to put systems and processes in place to ensure compliance with emerging and different standards around the world. In the long term, these companies need to make strategic decisions to reduce the complexity and cost of managing their global labeling content. This article discusses ways to alleviate these concerns through solutions that automate and integrate time-consuming, error-prone activities so that organizations are able to improve efficiency, quality, and content consistency across a broad range of products while still ensuring local regulations are met.


	FDA has spent several years developing the proposed ruling, which would be applicable only to pharmaceutical products that are marketed in the US. Under Section 1140 of the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA), legislators called on the Government Accountability Office (GAO) to study the pros and cons of scrapping the paper-based labeling for drug products and, instead, moving to an electronic system (2, 3). The study found both likely benefits and potential downsides to an electronic-based labeling system.

	There are several benefits to the proposed rule. FDA’s initiative to institute electronic labels in the US is aimed at ensuring the most current information is made available to HCPs and patients as quickly as possible. An electronic PI file will include the most up-to-date safety and efficacy information in real-time, which is not always the case with paper PIs, as updates take time to be reviewed, approved, printed, and distributed to the public. The electronic format will reduce the time taken for updates to get to patients and will enhance the accuracy of the labels.

	The existing process of developing a product label is human resource intensive and, therefore, requires extensive reviews and proofreading to ensure that the printed label is error-free. All of these factors significantly add to cost and time, not to mention the possibility of introducing manual errors.

	Several biopharmaceutical companies have expressed interest in distributing labels electronically. These companies think that it’s the right time to transition to an electronic PI from a static, potentially outdated paper version on pharmacy shelves and in the warehouses, to have the most current information electronically through a publicly available repository. In addition, it is estimated that the biopharmaceutical industry will save between $52 million and $164 million annually due to the proposed rule (4). FDA has come under fire, however, from patient safety groups and US legislators, who argue that the agency's attempt to require certain drug-labeling information to be distributed electronically could put patients at risk.

	The proposal does have disadvantages. Consumers, especially the elderly, might not know how to access the drug label online or might not have Internet access. Also, counseling patients might become more difficult for doctors who would no longer have access to printed package inserts (2,3). If patients do get a printed PI from their doctor the first time they are prescribed a medicine, they may continue to go by it even if the label has been updated with new information in electronic format.

	FDA would also need to amend the language that currently requires PIs to be located "on or within" the drug packaging, which would be a significant change. Other forms of patient labeling information, such as medication guides (MedGuides) or promotional labeling, however, are already allowed to be sent electronically (3).

	The proposed rule would apply to manufacturers, applicants, and persons who market prescription drugs that they regard as not subject to section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355). The rule aims to avoid the vast majority of the potential downsides identified in GAO's report by focusing on prescribing information intended for healthcare professionals.

	In proposing the new rule, FDA is ensuring that the most current PI for prescription drugs will be available and readily accessible to HCPs at the time of clinical decision-making and dispensing. The rule also requires that a product’s immediate container label and outside package include a statement directing healthcare professionals to FDA’s labeling repository to view the electronic version of prescribing information.

	Under the new system, product manufacturers or applicants will be required to update the product labeling at the 

 every time there is a change in the labeling. They would also be required to verify that the accurate, complete, and up-to-date labels are posted on the FDA website. Manufacturers would also be required to set up a 24/7 toll-free number where healthcare professionals could request paper copies of the prescribing information. This would ensure that persons without Internet access could still access prescribing information.


	The proposed rule from FDA has met with considerable criticism (5). Some safety groups, including the Institute for Safe Medication Practices (ISMP), have called the proposal unworkable in its current format. They state that the labeling repository website is not ready to use for locating drug information. The ISMP argue that the system is flawed and could potentially lead to harmful or fatal medication errors.  

	Additionally, another concern noted in many comments to FDA is that the electronic prescribing rule could impact the way in which physicians interact with and treat patients. ISMP noted that physicians frequently reference the printed materials and that change could lead to disruption in their workflow and even delay care during an emergency. Faced with a large amount of interest in the proposed rule, FDA announced on March 9, 2015 that it would extend the comment period for the proposal until May 18, 2015.

	US legislators have also written to FDA expressing concern about the proposed rule, highlighting that the paper inserts are an important tool for pharmacists and HCPs. They expressed concerns that the proposed rule could harm those living in rural areas where Internet access is poor.

Ensuring efficiency and compliance in product labeling


	Biopharmaceutical product labeling is specific in its content, especially with respect to efficacy and safety data and adverse effects. Additionally, the label needs to comply with country-specific regulations governing the product. A product label from an innovator pharmaceutical company, prior to commercialization, is drafted by the pharmaceutical company and is reviewed and approved by the applicable regulatory agencies, based on regulations and guidelines.

	On the other hand, a generic product label is based on the innovator label having already been approved by the regulatory authority. While a generic-drug company’s portfolio may include 300 products, the Reference Listed Drug (RLD) label could be sourced from 20 to 30 different companies, compounding the complexities in referencing and tracking of RLD updates. Labels are an essential part of the marketed product because they provide comprehensive information about the drug. They also represent a significant percentage of the manufacturing cost and commercialization risk.

	Moreover, a product with a wide geographical footprint would require labels in each country/region to comply with local regulatory guidelines. These multiple labels increase the risk of having non-uniform information disbursed globally for the same product. Each label update involves input from multiple stakeholders like regulatory, clinical, legal, quality, and manufacturing personnel. The sheer number of reviews makes data management, version control, and audit trails prerequisites to the labeling process.

	In conjunction with compliance to the requirements of multiple regulatory agencies, there is a constant need to address the challenge of ensuring consistency of content across a broad portfolio of products across multiple regions (6).

	FDA’s proposed rule will require manufacturers of prescription drugs to ensure that the electronic label is provided to FDA each time its content is changed; this requirement would result in pharmaceutical companies having to manage an overwhelming number of labeling records that are difficult to keep synchronized globally. It therefore becomes even more imperative that pharmaceutical companies make fundamental changes to their operations to adapt to the growing complexity, minimize risk, and improve efficiency of the labeling process, so that label updates are made in real time, globally.


	Labeling as a managed service is an externally managed, fully integrated platform of services, processes, and technology enablers that cover the entire labeling continuum. The service includes expert labeling resources that execute global labeling activities on behalf of a sponsor or generic-drug company; labeling processes that are monitored via key performance indicator metrics (KPIs) on performance, quality, and compliance goals; and preconfigured, ready-to-use technology solutions to support workflow and content management activities. A best practice labeling managed service model has benefits of efficiency, scale, and quality. Clients can use qualified external resources, processes, and integrated technology solutions to accelerate label development, updates, and implementation. Leveraging local and regional labeling knowledge and delivery capabilities aids in scale up. A managed service allows a client to forgo investments for internal resources and technology requiring optimization and customization and to maintain flexibility for scale-up and scale-down to manage costs.


	Successful organizations require a streamlined workflow-management model that includes document management, version control, and standardization/synchronization of processes such as labeling and artwork content across geographies.

	Having a portfolio of products across multiple regions means organizations must comply with the requirements of multiple regulatory agencies. Reliance on people-intensive, paper-based processes results in errors and time-consuming quality control activities. Moreover, each version of the product label requires its own artwork for the final printed label, necessitating another series of manual processes.

	Today, product labeling comprises disparate processes at different locations, based on country-specific preferences. A streamlined workflow management process, along with a document-management system that allows for version control and standardized label and artwork content, makes the task easier and more accurate, because it synchronizes content and versions across geographies. Organizations can outsource core labeling activities globally by partnering with a vendor with a global reach, who will work to assess the individual organization’s unique situation. They can build and implement a tailor-made solution, provide support throughout the product lifecycle, and ensure quality and compliance at a reduced cost (6).


	For biopharmaceutical companies, product labeling is a highly regulated and complex process that is an integral part of their overall quality system. This already complex process is complicated even further with the announcement of the proposed electronic labeling ruling. A product with a wide geographical footprint requires labels in each country or region to comply with the requirements of local regulatory agencies. Requiring electronic labeling increases the risk of having inconsistent information across labels of the same product. Failure to ensure these key requisites of label accuracy and quality can lead to labeling errors that are highly visible and can seriously damage the reputation of an organization.

Changes Proposed to Require Electronic Distribution of Package Inserts

, Jan. 22, 2015, accessed Mar. 23, 2015.	

FDA Proposal Calls for Drug Labeling to be Distributed to Doctors Electronically

," Regulatory Affairs Professional Society (RAPS), Dec. 16, 2014, accessed Mar. 23, 2015.	

Government Report Finds Mixed Opinions on Proposed Drug Labeling Overhaul

," RAPS, July 9, 2013, accessed Mar. 23, 2015.	

Electronic Distribution of Prescribing Information for Human Prescription Drugs, Including Biological Products

, Dec. 18, 2014, accessed Mar. 23, 2015.	

FDA's Electronic Drug Labeling Proposal Comes Under Fire

," RAPS, Mar. 25, 2015, , accessed Apr. 9, 2015.	


	Bindu Narang is director of Scientific Writing and Regulatory Affairs at Sciformix Corporation, 

Pharmaceutical Technology Outsourcing Resources Supplement

 When referring to this article, please cite it as B. Narang, “Implementing FDA’s Electronic Labeling Proposal,” 

Create an efficient global labeling strategy that is compliant with both electronic and paper-based package-insert requirements.