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On 12 April 2016, a group of 15healthcare stakeholders wrote to the USFood and Drug Administration (FDA)expressing concerns that the FDAProposed Rule to change generic druglabel requirements could create providerand prescriber confusion and addsignificant avoidable costs to an alreadystrained healthcare system.1

Nearly 8 in 10 prescriptions filled inthe US are for generic drugs. The use ofgenerics is expected to grow over the nextfew years as a number of popular drugscome off patent.2 Under regulations bythe FDA, generic drugs must bechemically equivalent, have the sameactive ingredients, and be bioequivalentto their branded counterparts.

However, the onus for safetymonitoring appears to rest on theinnovator, whose label is the ReferenceListed Drug (RLD). Most notably, while abranded drug manufacturer isresponsible for the accuracy andadequacy of its drug label, a generic drugcompany is responsible for ensuring thatits label is the same as the label of thebrand-name RLD.

Of several labelling regulationsexpected this year, the one with thegreatest impact would be the proposedrule regarding labelling of generic drugsby the US FDA. The proposed rule asksgeneric drug companies to update theirlabels with new safety information astheir reference product counterpartshave done for almost 30 years. The FDAannounced recently that this much-debated rule would be released in late2016, but the different genericstakeholders are protesting against it.

Existing labelling process complexitiesProduct labelling is a collaborativeprocess, from initiation of a clinical trialto commercialisation, with multiplesources of inputs that result in acompany core data sheet (CCDS). TheCCDS includes the minimum safetyrelevant information that needs to bepresent on the product labels and anylocal labelling information for differentgeographies are derived from this.2

Every local labelling document (LL)devised from the CCDS could bedifferent, depending on the geographicregions and on the product formulations.Complexity increases when these locallabelling documents are in a differentlanguage, with differing content. Theselocal adaptations also need to be updatedwhenever there is a change in the CCDSdue to availability of new safety, efficacyor product quality information andchanges in regulatory landscape.

Changing regulatory requirements andthe numerous hand-offs make the process

more complex. The existing process ofdeveloping a product label is humanresource-intensive, and, therefore,requires extensive reviews and proof-reading to ensure that the printed labelis error-free. All of these factors addsignificantly to cost and time, not tomention being fraught with thepossibility of introducing manual errors.

‘Failure-to-warn’ Today, the US FDA specifically requires ageneric product to have the same label asthe RLD. Therefore, even if the drugmanufacturer is aware of any safetyconcern, the label of the generic productcannot be updated unless the RLD labelis updated. This supports the businessmodel of the generic drug companies,since they do not need to engagethemselves in rigorous safety tracking

like an innovator pharmaceuticalcompany. It also largely grants thegeneric manufacturers immunity frombeing held accountable for notcommunicating key safety information tothe consumer, or ‘failure-to-warn’.

Under the proposed rule, genericmanufacturers will need to monitorsafety events actively, and update the

labels on receipt ofnew safety-specificinformation, byfiling a CBE-0. Thisrule may then makethe genericmanufacturersaccountable in‘failure-to-warn’cases and therefore,encourage thegeneric

Bindu Narang, Director of Regulatory Affairs and ScientificWriting, Sciformix Corporation, considers the impact of proposedUS FDA labelling regulations on the generic drugs sector

Labelling andgenerics: who isaccountable?

“Complexityincreases whenthese locallabellingdocuments arein a differentlanguage, withdifferingcontent”

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June 2016 manufacturing chemist 27

strategy, yet often these three elementsare not in sync. Quality and complianceare mandatory, yet the resources,processes and costs required to meetthese demands are a significant burden.

A product label from an innovatorpharmaceutical company, prior tocommercialisation, is drafted, thenreviewed and approved by regulatoryagencies, based on regulations andguidelines. Label maintenance, includingsafety updates, is an essential part of theinnovator’s marketed products since theyprovide comprehensive informationabout the drug. They also represent asignificant percentage of themanufacturing cost andcommercialisation risk.

On the other hand, a generic productlabel is based on the innovator labelhaving already been approved by theregulatory authority. While a genericcompany’s portfolio may include 300products, the RLD label could be sourcedfrom 20 to 30 different innovatorcompanies, compounding thecomplexities in referencing and trackingRLD updates. Labels are an integral partof the marketed product. They alsorepresent a significant percentage of themanufacturing cost andcommercialisation risk.

Labelling as a Managed ServiceLabelling as a Managed Service is anexternally-managed, fully integratedplatform of services, processes andtechnology enablers that covers theentire labelling continuum. The serviceincludes expert labelling resources thatexecute global labelling activities onbehalf of a sponsor or generics company.

Oversight of the labelling workflow viakey performance indicators (KPIs) andquality metrics can ensure anorganisation is compliant with local andglobal regulations and efficient.

By employing a managed servicemodel, potential clients can reap thebenefits of end-to-end labelling workflow.Today, product labelling comprisesdisparate processes at different locations,based on country-specific preferences. Astreamlined workflow managementprocess, along with a documentmanagement system that allows forversion control, and standardised labeland artwork content, makes the taskeasier and more accurate, since itsynchronises content and versions acrossgeographies.

Organisations can ensure scale,performance, quality and compliance forlabelling activities through a managedservice by partnering with specialisedservice providers with global reach sothat local regulations are also met.

In summary, for generic manufacturersthis proposed rule is a compelling reasonfor implementing processes for safetylabel updates and improved safetytracking, as they become increasinglyaccountable for ‘failure-to-warn’ cases.From a patient’s perspective, this is apositive step in terms of equippingconsumers with most up-to-date safetyinformation. However, increased safetytracking may lead to increased cost toconsumers.

As the FDA makes it clear the rule willbe rolled out later this year, it is expectedthat current hurdles will be solved,despite the controversy it has caused.

REFERENCES1. Dr. Robert Califf, 2016. (Internet)http://www.gphaonline.org/media/cms/April_2016_Generic_Labeling_Allies_Letter_1.pdf [Accessed17/04/2016]2. FDA, 2016. Facts about Generic Drugs (Internet)http://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/understandinggenericdrugs/ucm167991.htm [Accessed 17/04/2016]3. The Hatch-Waxman Act--25 Years Later: Keepingthe Pharmaceutical Scales Balanced, Martha M.Rumore, PharmD, JD, FAPhA, August 15, 2009(Internet) http://www.pharmacytimes.com/publications/supplement/2009/genericsupplement0809/generic-hatchwaxman-0809 [Accessed17/04/2016]

CONTACTSciformix Corporation1500 West Park DriveSuite 210, WestboroughMA 01581USAT +1 877 576 5005www.sciformix.com

“For genericmanufacturersthis proposedrule is acompellingreason forimplementingprocesses forsafety labelupdates andimproved safetytracking”

manufacturers to track the safety of theirproduct more rigorously. Given theimplications of this proposed rule, it hasmet with strong reactions from theindustry, with more than 23,700comments.

One of the concerns has been that the‘identical nature’ of the generic drug tothe reference drug has been the reason forphysicians to use the generic drugs withconfidence. Also, the proposed rule wouldincrease healthcare costs for consumersand government agencies due to theadditional resources, processes and toolsgeneric manufacturers will have toimplement for enhanced safety tracking.

As the release date nears, the FDA itselfwill need to overcome issues that ariseowing to the conflict between theproposed rule and the concept of genericsas described in the Hatch Waxman Act.3

From a patient’s perspective, the newregulation is a step in the right directionin terms of equipping them with mostupdated safety information, but it mayincrease the cost of generic drugs. For thegeneric manufacturers, this rule hassignificant implications as they will berequired to implement a safety trackingsolution and processes for safety labelupdates.

If and when the new ruling takes effect,generics companies will need to ensurethey strengthen their pharmacovigilanceoperations and enforce rigorous safetymonitoring. Quality, efficiency andcompliance must be underscored in anorganisation’s labelling operations

Bindu Narang, Director of Regulatory Affairs andScientific Writing, Sciformix Corporation