 Fig. 1. (a) Total number of injectable new molecular entity (NME) approvals by FDA by year and molecule category. (b) FDA injectable NME approvals by category as a percentage of all injectable NME approvals. The trend lines are to guide the eye. Source: fda.gov. Note: 2017 values are year-to-date as of August 2, 2017.[/caption]

More than 30 years after the first FDA approval of a therapeutic monoclonal antibody (mAb) in 1986, these recombinant protein drugs are beginning to deliver on their potential to revolutionize medicine. Therapeutic antibodies are a manifestation of remarkable advancements in biotechnology and, due largely to their specificity in binding to target molecules, they are having substantially positive impacts on treatment outcomes. Drugs targeting auto-immune diseases such as adalimumab (tradename, Humira®) for rheumatoid arthritis, are improving the quality of life for chronic disease sufferers. [Schiff 2014] Oncology drugs such as trastuzumab (tradename, Herceptin®) are significantly improving long-term progression-free survival rates in cancer patients. [Swain 2015]

With the clinical success of this class of drug molecules, the number of FDA-approved monoclonal antibodies (and closely associated recombinant proteins such as antibody-drug conjugates and Fc-fusion proteins) is growing fast. Antibodies represent the majority of new biologic drug approvals and biologics represent the majority of new injectable drug approvals. Figures 1a and 1b show the injectable New Molecular Entity (NME) approvals since 2011 (where 2017 data represents year-to-date as of August, 2017). Biologic and specifically antibody approvals are increasing, both in absolute number and as a percentage of all injectable drugs.

Since the bioavailability of proteins delivered by oral dosage or inhalation is poor at present, mAbs and derivatives thereof are delivered by injection. This is in contrast to innovative small molecule drugs, which can be more readily delivered in oral dosage forms. Hence, mAbs are typically packaged and stored in liquid or lyophilized format in glass vials, prefilled syringes or cartridges for later injection.

Now that these targeted treatments have been proven for a number of disease states, additional focus can shift toward outcome optimization as it pertains to safety, efficacy and patient experience. There is growing appreciation for, and concomitant scrutiny over, the stability of therapeutic proteins during storage/delivery and how stability issues may impact the safety and or efficacy of the drug product. Stability is the number one objective for mAb formulators and can even impact which molecular candidates advance at the discovery stage. A molecular entity with better stability may preferentially advance over a molecular candidate with higher affinity to the target but lower stability. [Sievers 2017] In such a case, affinity may be optimized in later discovery/development cycles. Despite efforts to achieve the best stability at the discovery and formulation stages of drug development, there are numerous challenges that can be introduced by the packaging/delivery systems.

Proteins are designed by nature to be interactive with and responsive to their environment, and thereby highly subject to chemical and conformational changes. They can have numerous reactive functional groups that may be prone to oxidation, deamidation and other chemical modifications. The same protein can simultaneously carry regions of hydrophobicity, as well as regions of positive and negative electrostatic charge. As a result, proteins can interact with nearly any surface or interface that they encounter whether solid, liquid or gas, and no matter the material (metal, glass, polymer, air, silicone etc.). The interaction can leave the protein wholly unaffected or lead to reversible or irreversible adsorption, chemical or conformational changes, and/or aggregation.

Surfactants are a key element in controlling and maintaining protein stability—especially in the presence of silicone oil. Polysorbate 20 or polysorbate 80 are often used in low concentration by mAb formulators to mitigate protein adsorption at interfaces. Because surfactants are so important to maintaining protein stability, FDA considers them to be critical excipients. [Singh 2017] Furthermore, while they may provide an easy solution to stability challenges, polysorbates are complex raw materials that may contain significant variability in their purity/composition, cause new leachables to appear, and can degrade into free fatty acids that themselves can impact formulation stability. [Singh 2017] Rather than fully relying on surfactants to stabilize a formulation, it may be desirable to minimize the interfacial interactions that can impact stability.

In a vial, prefilled syringe or cartridge, aside from the container walls and elastomer surface, a therapeutic protein may be exposed to thousands of micro-interfaces that can be introduced by air or silicone oil. For example, agitation during shipping and handling can entrap air bubbles which can introduce thousands of new liquid-gas interfaces into the formulation. Furthermore, in a prefilled syringe or cartridge, silicone oil droplets can represent an additional population of micro-interfaces with which a therapeutic protein may potentially interact. Regardless of their nature, thousands of micro-interfaces in a formulation can represent a risk to protein stability, and from this perspective, silicone oil has been the subject of great scrutiny for more than a decade.

Industry opinions on the topic of silicone oil in prefilled syringes vary widely from drug company to drug company (even from person to person within a company) and can range from, “Silicone oil? None for me, thanks,” (indicating a strategy to completely eliminate the risk) to, “I’ve never met a protein that I couldn’t formulate around,” (indicating a strategy to contain the risk). While some proteins are highly silicone-oil sensitive (meaning that aggregates readily form when silicone oil is introduced; abatacept [tradename, Orencia] is one such example), many proteins are not. Nevertheless, ideally, rather than excluding viable molecular entities at the early discovery stage due to silicone oil sensitivity, or relying on surfactants to mitigate the risk, it seems desirable to altogether eliminate this micro-interface-creating lubricant from the packaging systems.

Completely silicone-oil-free syringe and cartridge options for parenteral drugs have historically been a technological challenge. Given the industry-wide investments in bricks-and-mortar fill/finish equipment, primary containers that radically differ from a traditional prefilled syringe or cartridge format are difficult to adopt. Within the confines of a traditional syringe/cartridge configuration, the challenge of eliminating silicone oil then centers around managing the frictional forces at a piston-barrel interface while maintaining seal integrity during storage. In a traditional syringe, friction is managed to acceptable levels by lubricating both the barrel and the plunger with silicone oil which can migrate into the formulation as “free” silicone oil droplets (thousands of micro-interfaces).

Incremental and often significant improvements towards reducing free silicone can be achieved through baked-on silicone technology or other fixed lubricants on the barrel and/or plunger (Fig. 2). It is important to note that those applications demanding a reduction or elimination of silicone oil from the primary packaging materials (i.e. therapeutic protein drugs) are the same products that simultaneously demand barrier-coated elastomers. Ever since the infamous situation surrounding Eprex and an increase in incidents of red cell aplasia in kidney disease patients, [Bovin 2005] barrier-coated elastomers are the standard for primary packaging of biologics. Therefore, the ideal syringe or cartridge system should combine both the attributes of silicone-oil-free and barrier-coated elastomers. The Daikyo Crystal Zenith® (CZ) syringe is currently the only commercial offering that delivers these two critical attributes together in one package. (Fig. 2)

Today, the vast majority of biologic drugs are packaged in glass primary containers and those that utilize prefilled syringe or cartridge formats are siliconized. There are no commercially available prefillable glass syringe or cartridge systems that are able to function in the absence of a barrel lubricant. Numerous suppliers offer polymer syringe and cartridge systems comprised of either cyclic olefin polymer (COP) or cyclic olefin copolymer (COC), which are also siliconized. While polymer syringes derive value from mitigating risks related to glass breakage, they have traditionally struggled to gain significant market share. In general, the main reason for this is that the value of engineered polymer containers is not perceived to sufficiently exceed glass such that the change can be justified. Combining the break resistance of COP, the complete absence of silicone oil, along with the utilization of barrier coated elastomeric closures, as in the Daikyo CZ syringe, together can change the value proposition around engineered polymer systems.

As shown in Figure 2, the Daikyo CZ syringe utilizes a Flurotec barrier coated plunger in combination with a proprietary cyclic olefin polymer (COP) barrel. Together, these two components represent an effective strategy for managing frictional forces in the absence of silicone oil while simultaneously providing sealing properties. The Flurotec fluoropolymer film acts as a dry lubricant and the COP barrel, in contrast to glass barrels, provides a smooth surface with very tight tolerances and nearly zero draft. In tests with unfilled syringes, hydrodynamic forces (the forces associated with a fluid passing through a needle for example) are essentially eliminated and friction forces can be directly measured. What can be observed from these tests is that the magnitudes of the static and kinetic frictional forces (break loose and extrusion forces) are low and the profiles are highly consistent from sample to sample.

The smooth COP barrel surface and the dry lubrication of the Flurotec film proves to be an effective way to manage the frictional forces in the absence of silicone oil, and the elimination of this fluid lubricant can have a significant, positive impact on the stability of sensitive protein drugs. Orencia is a 92 kDa fc-fusion protein with known silicone oil sensitivity. (The package insert for the lyophilized version of this drug product stipulates that for its reconstitution and delivery, a silicone-oil-free [disposable] syringe must be utilized.) As such, this molecule represents a suitable model for investigating the impact of eliminating silicone oil from a prefilled system. Figure 3 shows the measured turbidity (absorbance at 350 nm) of WFI-reconstituted (water for injection) solutions of 2.5 mg/mL Orencia that were stored in either siliconized glass syringes (grey bars) or Daikyo CZ syringes (blue bars) and agitated by continuous end-over-end rotation for up to 48 days. The pink bar at 48 days shows a control solution that was stored in an unsiliconized glass tube at 4ºC without agitation. The silicone sensitivity of Orencia is demonstrated by the increase in turbidity due to aggregate formation observed with the siliconized glass syringes. But even under extreme agitation conditions, the Orencia solution shows no increase in turbidity versus the control when stored in Daikyo CZ syringes.

 Fig. 3. Turbidity (UV absorbance at 350 nm) of a WFI-reconstituted solution of 2.5 mg/mL Orencia® (abatacept) stored in either siliconized glass syringes (grey bars) or Daikyo Crystal Zenith® syringes (blue bars) after continuous end-over-end rotation (extreme agitation), at room temperature for up to 48 days. The pink bar at 48 days shows a control solution, unagitated, stored at 4ºC in an unsiliconized glass screw-top container.[/caption]

Arguably, it took more than 20 years for mAbs to start changing the paradigm of disease treatment. In such a risk-adverse industry, the development, acceptance and commercial implementation of new parenteral drug packaging materials can move even slower than the evolution of drug technologies. What will accelerate change will ultimately be the realization of a better fundamental understanding about how primary packaging can impact patient safety and drug efficacy. As this understanding grows and evolves, mAb producers continue to focus on eliminating risks wherever possible to ensure the fastest time to market for their drugs. The Daikyo CZ technology offers a strategy for de-risking the discovery and development of therapeutic protein drugs through the elimination of a fluid lubricant, utilization of barrier-coated elastomers, the clean manufacturing process of COP (no tungsten or glue), and the full commercial offering of silicone-oil-free containment from vial to prefilled syringe to cartridge for easy lifecycle management. Early drug candidates that are silicone sensitive would not have to necessarily be de-selected from the discovery process. Daikyo CZ engineered polymer containers also de-risk the safety and financial impacts related to glass breakage at the site of filling or during storage/shipment/handling.

To date, there have been more than 35 global regulatory approvals of parenteral drugs packaged in Daikyo CZ vials, syringes and cartridges in the United States, Europe and Japan with numerous pipeline candidates in development. Demands for higher quality, cleanliness and performance combined with an increasing understanding of how to maximize the probability of clinical and commercial success, may ultimately drive significant change in the paradigm in primary packaging towards silicone-free polymer containers for a broad range of therapeutic protein drugs and beyond.

A. Sievers. Early Discovery biophysical analysis of proteins to enable selection of better therapeutic molecules. Colorado Protein Stability Conference, 2017.

M. Schiff, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Ann. Rheum. Dis. 2014; 73: 86–94.

S. Swain et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer. N Engl J Med 2015; 372: 724–734.

S. Singh. Surfactants in Biotherapeutics: Can’t live with them, Can’t live without them. Colorado Protein Stability Conference, 2017.

K. Bovin et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney International. Volume 67, Issue 6, June 2005, Pages 2346–2353

Susan M. Dounce, Ph.D., is subject matter expert, Prefilled Syringes, Crystal Zenith®, and Combination Products at West Pharmaceutical Services, Inc. Prior to joining West, Susan held various technical, commercial and academic roles in the healthcare industry with Dätwyler, W.L. Gore, and as an adjunct professor at Temple University. She also serves as vice chair for the PDA Packaging Science Interest Group. She holds a B.S. in Chemistry from the University of Rochester and a Ph.D. in Physical Chemistry from the University of Pennsylvania.

Articles

The changing paradigm in primary packaging of therapeutic proteins

At the beginning of this year, Pharmaceutical Commerce called 2017 “Year Zero” in the march toward end-to-end pharma traceability. The ostensible reason was that November 2017 was to be the date when effectively all new pharmaceutical packages entering US commercial distribution were to have a unique serial code on them. An insider’s reason was humor: pharma traceability has been progressing, with much backtracking, for over a decade, ever since guidances came out of FDA in the early 2000s recommending some way to identify the “pedigree” of authentic products in distribution. (Historians can note that counterfeit healthcare products became an issue at multiple times over the 20th century, even predating FDA. In the 19th century, there actually was “snake oil” as a healthcare product—and it was counterfeited, too.) Traceability has been a never-ending journey for the pharma industry.

Well. Soon after the “Year Zero” label was applied, FDA announced a one-year delay to enforcing the November 2017 requirement. (We’ll hold off on calling 2018 Year Zero, Year One or anything else!) So now, under the mandates of the Drug Supply Chain Security Act of 2013 (DSCSA), the serialization will occur in 2018, to be followed by requirements among US wholesaler-distributors and others to verify the authenticity and sell-by dates of drugs they receive by 2019. Pharmacies and health systems have requirements to be met during 2020–2022, and everything is supposed to be digitized, recorded and verifiable by 2023.

The US activity is paralleled by the Falsified Medicines Directive (FMD) in Europe, and similar efforts in approximately 40 countries around the world that will apply some level of traceability to pharma packages. Europe’s effort goes back to an initiative set in 2011; the date when packages in distribution are to be verified at the point of dispensing is February 2019. Most countries around the world are holding closely to the US model of tracking pharma shipments point by point; the European model, coming out of the parallel trade policies in the European Union (which are intended to streamline trade between EU members) is a so-called “bookend” approach that verifies package authenticity at the point of origin and point of dispensing, but leaves out most of what happens in between.

The specific goal for FMD’s promulgation is to minimize or thwart altogether the entry of counterfeit products into commercial distribution. That’s the ostensible goal of DSCSA as well; however, as critics of the DSCSA effort have maintained all the way back to the early 2000s, counterfeit product is a relatively insignificant part of US distribution. While the DSCSA system will also hinder counterfeit introductions, commercial managers in pharma see potential value in minimizing drug diversion, where distributors shift products intended for one commercial channel (and one price) into another (and another price). Achieving Amazon- or Walmart-like supply chain efficiency and transparency is also a potential benefit.

There has been relatively little regulatory action since FDA announced the one-year postponement of serialization requirements, and at the time, the delay elicited only a subdued response. FDA is behind schedule on several guidances that were supposed to be issued; one thing it did do last spring was to reopen a request for comments on proposed pilot projects to demonstrate industry capability to meet the 2023 goals (the first request was made a year earlier). The comment period ended in September, but FDA has yet to announce an actual solicitation.

Some of the industry commentary was that pilots have been successfully carried out (by Johnson & Johnson, and by a joint project of the Healthcare Distribution Alliance and wholesalers and manufacturers: the “Saleable Returns Pilot” to test the ability to process items returned to wholesalers from retail pharmacies). Other comments—such as from the community and chain pharmacy sector—were to caution FDA that the technical requirements of DSCSA are likely to be beyond the capability of many pharmacies (the National Assn. of Chain Drug Stores noted that “there are some small dispensers that do not even have an IT department. For any pilot project to work on a larger scale, those running the pilot project must ensure that they test whether the pilot project will work for even those with the most basic IT capabilities.”

FDA is scheduled to hold a second and third public workshop at FDA headquarters on Dec. 6 and Feb. 28.

While there has been intense wrangling over the processes for managing traceability data throughout the supply chain, the initial step—encoding pharma packages with 2D barcodes—has many commercially demonstrated installations up and running. A large and growing set of vendors provide this equipment, and most manufacturers have functioning packaging lines. Over the past couple years, there had been concern that contract manufacturing organizations (CMOs) were far behind the major manufacturers in serializing their lines, and while there are still many not yet equipped, the picture is considerably better now. TraceLink, one of the leading vendors of network serialization software, announced in mid-October that more than 100 CMO’s were linked to its platform, the TraceLink Life Sciences Cloud (presumably, a CMO wouldn’t do this unless it were able to produce serialized packages on its lines.)

An industry standardization effort, initiated by packaging equipment vendors but now with a number of manufacturers and enterprise-software vendors participating,* announced a helpful industry standard for data exchange between a manufacturing site and the business enterprise, i.e., Level 3 and 4 (Fig. 1). The Open-Serialization Communication Standard (Open-SCS) Working Group is in the process of publishing a voluntary standard, “Packaging Serialization Specification 1.0” (PSS 1.0).

PSS 1.0 aims to resolve communication variations among IT systems handling Level 3 (plant or distribution center sites) and Level 4 (corporate enterprises) for four common use cases:

To date, the IT traceability systems of such vendors as TraceLink, Systech, SAP and others have their own methods for carrying out these functions; it is easy to envision a scenario where serialization systems of different vendors co-exist under one enterprise, or—a common situation—where the serialization processes being carried out at a contract packaging organization need to be communicated to the enterprise client of the contractor. In theory, having a common standard for these communications will simplify the implementation of serialization systems, reducing implementation costs, and give packagers more flexibility in mixing and matching the various IT solutions. Vendors are also looking at a global serialization mandate, where various countries are putting their own spin on what data needs to be reported to whom.

Optel Vision, which organized an industry meeting in 2014 on the interoperability topic, has been pushing hard for serialization vendors to come together on the standards. “As a systems integrator of packaging-line serialization, we estimate that between 500 and 1,000 hours are needed to build interfaces among the various pieces of equipment and software systems,” says JP Allard, global serialization program manager at Optel Vision. “Standardization could cut that down to 30–50 hours, with added benefits later on as software and hardware upgrading occurs.”

PSS 1.0, according to announcements at September’s Pack Expo meeting, will be formally issued in November, and will include functional specifications, IQ/OQ templates, a validation test and a certification plan, among other elements. The working group is finalizing documentation, running a multi-vendor test and setting up the certification program. “This important announcement follows more than two years of committed collaboration by our technical group,” Marcel de Grutter, executive director of the Open-SCS Group (and an IT manager at Abbott). “Now that the initial standard is released, we are hoping for its expedient adoption across the industry: that will be our next challenge.”

Open-SCS is not done, by any stretch. Plans are already in place for PSS 2.0, intended to address communications issues between Level 3 and Level 2 (the packaging line; i.e., controllers and smart devices on the line). Use cases are still being determined; presumably, this standard will encompass nagging serialization issues like parent-to-child relationships among serial numbers (e.g., when multiple units are aggregated to a single case). PSS 2.0 is scheduled to arrive during 2018.

A helpful aspect of PSS 1.0, and the Open-SCS Working Group overall, is simply to bring the serialization process into a format that industrial automation vendors are accustomed to in other aspects of pharma manufacturing—specifically, the Level 1-4 “stack” of automation levels. This terminology is common to the automation frameworks of organizations like the International Soc. of Automation (ISA), with which Open-SCS is coordinating its activities. It’s reasonable to ask why this standardization didn’t occur five or more years ago as serialization systems began to be installed; better late than never, one can assume. Then there’s the question of where the GS1 standard for serialized supply chain events (EPCIS) leaves off and Open-SCS steps in.

Brian Daleiden, VP of industry marketing at TraceLink, says that there is a “synergy” between EPCIS and PSS 1.0. Dirk Rodgers, regulatory strategist at Systech International, says that EPCIS is mostly about data-sharing between trading partners, while PSS 1.0 handles data moving up and down in the packaging process.

All that being said, the Open-SCS group represents progress in establishing serialization technology. Customers of this technology will do well to check the certification status of their vendors going forward.

 Fig. 2. The workflow for data moving between the various automation levels within a site, and from the site to the enterprise, as defined by the Open-SCS Group. Credit: Open-SCS[/caption]

As the 2023 finish line gets closer, the debate over how traceability data in supply chains is to be handled has intensified. With Europe’s FMD, the issue is relatively straightforward, helped along by the fact that most of Europe manages pharmaceutical reimbursement through a single, national payment system. Already, the European Union set up a quasi-governmental organization, funded and operated by manufacturers and supply chain participants, the European Medicines Verification Organization (EMVO). Although the mechanisms are still being developed, and there are some variations from country to country in the system, each EU member has a central repository of stored product identifiers. Pharmacies and other end purchasers of pharmaceuticals are to verify the product ID against the national database, and the authentication process is essentially complete. A pan-European data repository acts as a switching point to route verification requests from one nation’s repository to another’s.

In the US, FDA has hinted at getting such a central repository set up, but most industry players are adamantly opposed to this, preferring some type of distributed data repositories. “A centralized system with the ability to see and know a product’s status at any point in the supply chain would also require trading partners to undertake actions the DSCSA does not mandate,” wrote Anita Ducca, HDA’s SVP, regulatory affairs, in comments to an FDA solicitation this year. “Data access, ownership and security would also pose significant hurdles … [and] because of the volume of participants, including dozens of wholesale distributors, hundreds of manufacturers, and hundreds of thousands of dispensers, we anticipate obtaining industry-wide participation in such a system, and governance of it, to present very significant challenges.”

There’s some irony, then, in an effort undertaken by HDA itself to bring some scale and efficiency to data exchange has now entered the courts. This summer, HDA set up a hosted (by ValueCentric, an IT company with long experience in managing pharma supply chain EDI data) database, Origin, to store the GTIN identifiers of products entering commercial distribution. GTINs are not, themselves, the complete traceability record of a package (that would be a serialized GTIN, or sGTIN, plus transaction history information). In late October, TraceLink filed suit in federal court* against HDA.

* There are 25 members currently: Abbott, ACG Inspection Systems, Adents, Advanco, Antares Vision, Arvato Systems GmbH, ATS Global, FacilityBoss, Giesecke & Devrient, Laetus, Mettler Toledo PCE, Omron, Optel Vision, Pfizer, Roche, Rockwell Automation, SAP, Systech International, Tradeticity, Teva, TraceLink, Uhlmann, Vantage Consulting, Werum, and Wipotec-OCS.

TraceLink’s case alleges that Origin is a “conspiracy” by HDA to monopolize product identity information. HDA’s intent, it is claimed, is to “coerce” its members (which constitute the vast majority of primary wholesaling in the US) to use Origin, and has set up “exclusionary license contracts” to hinder pharmacies and other supply chain participants from using alternative products, specifically TraceLink’s Life Sciences Cloud. Already, says TraceLink, “a number of TraceLink’s customers have discontinued their subscription to TraceLink’s Life Sciences Cloud to date, with an unknown number of them switching directly to the HDA’s competing solution.” Earlier this year, TraceLink set up what appears to be a comparable offering, the Network Product Master Data Service, which includes a capability to discover NDC data among its hundreds of clients and make that available to other members of the network.

TraceLink seeks to enjoin HDA from making participation in the Origin data repository mandatory, and to recover $30 million from HDA for damages. “We are reviewing the complaint and do not have any further comment at this time,” according to an HDA spokesman.

When Origin was announced, HDA seemed to be clear that the repository was a database only of identifiers, the so-called Global Trade Item Number (GTIN—and specifically, the GTIN-14), which does not include either unique serial numbers, or transaction history information. TraceLink’s suit acknowledges some of this, noting that Origin “is solely a data repository that identifies specific packages of drugs that have been put into the supply chain,” and that “to the contrary, the Life Sciences Cloud provides the user not only with this information, but also with information regarding, among other things, when and to whom the product was sold.” However, that word “specific” in the TraceLink statement points to serialization data.

TraceLink’s suit goes on to note that the use restrictions on Origin “which in the very least require users of competitive track and trace solutions to incur substantial opportunity costs by forcing them to re-enter their data into the competitive systems, effectively prohibit manufacturers and distributors from dealing with competitors, like TraceLink.” And this points to a workable, if onerous, solution: either HDA makes the Origin data available to companies like TraceLink, or TraceLink customers go through the process of entering their GTIN data with both Origin and with TraceLink’s Life Sciences Cloud. Obviously, such duplication of effort runs against the grain of DSCSA, in that it is highly problematic for two data repositories to be exactly identical. (The alternative, that TraceLink be the sole repository of GTIN data, is equally problematic, given that there are numerous competitors to TraceLink.)

“The issue is not over data ownership,” says Shabbir Dahod, president and CEO of TraceLink, “but is about creating an open, interoperable system for GTIN data that allows all solution providers, including TraceLink, to compete” versus what is said to be the closed, proprietary system that HDA has created. “GTIN information is at the core of what must be shared, by trading partners or by vendors like ourselves to service the industry.”

Seemingly from left field, a relatively new technology—the “distributed ledger” technology commonly known as blockchain—is generating more interest among traceability experts (Pharmaceutical Commerce, July/Aug, p. 22). The inherent nature of blockchain is a network of linked databases, with cryptographic methods to store time-stamped data, such that altering the data undetected is virtually impossible. As applied to pharma traceability, blockchain could enable trading partners to exchange transaction data of serialized pharma shipments with each other, with an “immutable” record of the transaction, and with the record being “hashed” (cryptographically encoded) so that the trading partner originating the message can protect all or part of it from others’ view. It is also possible for a blockchain network to run without any central authority, although most conversations about the application involve some method to validate who can participate in the network.

One indicator of interest in blockchain is its growing interest at HDA. From a one-hour session at the 2016 Traceability Seminar, this year’s meeting will feature a five-hour workshop on the technology. Also, the Institute of Electrical and Electronic Engineers (IEEE) held a meeting in mid-2017, with more in the works.

Bob Celeste, a former GS1 US Healthcare manager and now principal of a consulting firm called the Center for Supply Chain Studies (www.c4scs.org) has run a series of study projects on the topic, with a proof of concept study scheduled for 2018. Work to date has determined the six challenges the topic currently faces in pharma traceability:

To establish an electronic connection between non-adjacent trading partners

To establish trust between these trading partners

To share required data without exposing proprietary data

To support traceability activity at trading partners

To design for expansion beyond DSCSA compliance

A feature of C4SCS’ approach is to use simulation modeling tools for network activity: “Study participants suggest use cases or modifications to traceability activity, and the model can determine what is feasible,” he says.

Another effort has been announced by a partnership of two San Francisco startups: The LinkLab LLC and Chronicled, who have developed a prototype blockchain called MediLedger. Genentech, Pfizer, AbbVie, AmerisourceBergen and McKesson have participated in the endeavor to date. Susanne Somerville, co-founder of The LinkLab, says that the prototype is “blockchain agnostic” (i.e., of the variety of blockchain frameworks in existence, there is no preferred version as yet), but the prototype work has been performed with Quorum, an offshoot of the Ethereum protocol, which is supported by J. P. Morgan and Microsoft, among others. Interestingly, both the C4SCS and MediLedger projects, as well as a blockchain effort by Unisys, are looking at pharma cold-chain logistics as a test case for applying the technology to life sciences. A progress report is promised from LinkLab before the end of the year.

FDA plods along; industry builds out barcode installations, and IT experts pay closer attention to blockchain technology

Traceability end-of-year update

 Fig. 1. Simulated environmental conditions for a pallet-size shipment covered with a palletquilt; through its temperature cycling, the payload maintained specified temperature for up to 72 hours. Credit: QProducts & Services[/caption]

Meeting the challenges of ensuring product integrity, while keeping control of transportation costs, is a common responsibility for life sciences supply chain managers. This responsibility requires a finger on the pulse of both equipment cost and availability, combined with a true understanding of product stability and the shipping network it travels on. Where, when and how your shipment travels is the key to shipping with confidence. Quantifying risk versus costly equipment at a time when refrigerated capacity is causing rates to soar can be a real challenge. Compound this with products monitored for controlled room-temperature (CRT) specifications and maintaining the cold chain can get expensive quickly.

You can provide your supply chain with another viable option to increase flexibility and reduce transportation costs: employing passive thermal blanketing as an alternative to refrigeration equipment. Best practice is to understand the environmental conditions of a shipping lane, the stability characteristics of the payload, and predictive analytics for anticipating and preventing thermal excursions.

The savings are real, and believe it or not, Big Pharma has been using thermal blankets and covers to send pallets of temperature-sensitive freight on dry equipment for years. [1] One of the original players in the passive thermal protection industry, QProducts & Services (QPS), has been in the business for more than 20 years selling their CargoQuilt, PalletQuilt and other branded products to the food, beverage and chemical industries to protect their products from extreme heat and cold over land, air and ocean. “We didn’t know in the early years that all the time and effort put into product design, product testing and ambient temperature studies for the food & beverage industry would eventually play such a big part in protecting many of the healthcare products we use today,” says Jim O’Donnell, director of sales for the company’s life sciences market.

More recently, QPS has partnered with a UK firm, TP3 Global, to bring their SilverSkin reflective blanket covers to the US market, offering a wider range of technical options for the life sciences industry.

“As we all know now, the healthcare industry is required to follow Good Distribution Practices (GDPs) in many parts of the world. The cold-chain 2–8°C product always had to be protected, but now there is a newly required CRT temperature range, generally defined as 15–25°C. QPS has attended many healthcare conferences and joined healthcare groups that all have the same concern over there not being enough temperature-controlled equipment in the world to transport all this product that was never protected before. Even if the equipment was available, the cost would be unthinkable. Big Pharma required Big Help with this task,” O’Donnell adds.

Many questions need to be answered, such as: how hot or cold does it get in a trailer, in an overseas container or on an airport tarmac? And ultimately, could land, air and ocean CRT products be protected with thermal covers? The simple answer is yes, but with many important details to consider. “You have to be willing to work with an experienced supplier who will take the time to understand your specific challenges,” says O’Donnell. “Sometimes we learn with the shipper or manufacturer what is really happening before, during and after transit of their freight and how it’s actually affecting the product.” The recipe for success is to know your product, know your shipping environment and know your technology.

Healthcare products are put through temperature stability testing determining the safe temperature range for a given product. Some products are labeled 15–25°C and cannot go above or below that temperature. Others may have the same label, but can have allowable temperature excursions for a specified time limit. When considering passive temperature protection, this information is essential for designing adequate protection.

To understand passive temperature protection, you first must understand the effects weather has on the shipping environment. Know what temperatures your products are exposed to and for what length of time. For example, if the temperature outside is 85°F, how hot is it in a trailer that has been sitting in the sun for six hours in a parking lot? Does the temperature change if the truck is moving? Is there a difference between trailers and containers? Containers are shipped over land and sea, and for longer periods of time. How does this impact the internal shipping environment? Airfreight that sits outside waiting to be put on a plane is another set of environmental conditions to consider.

Make sure you work with a company that has years of experience in this area, are experts in passive thermal protection and have the answers to these questions, as well as the many others related to the mode and lane your shipment travels. “The idea is to avoid using a cover designed to protect for three hours in the sun on a shipment that requires three days of protection in a trailer. On the flip side, you don’t want to spend the money on a thermal cover designed to protect for days when your window for temperature excursion is only three hours on the tarmac,” says O’Donnell.

QPS has added to its consultative services by partnering with Riskpulse, a meteorological firm to analyze weather conditions regionally and nationally in predicting temperature conditions in trade lanes.

Behold the price-performance continuum (fig. 2) portraying the cost and effectiveness of passive thermal protection products. With many shapes, sizes, benefits and features, it all comes down to what level of performance you need in order to validate and approve the protection you can count on. With a simple cover for starts and finishing with a hard-shelled, fully insulated shipping box, the cost variance is extreme. Passive thermal technology relies on some basic principles of thermal dynamics: radiant, convective and conductive heat, and inversely the loss thereof.  A proven solution for both convective and radiant heat can be found on the lower end of the continuum and include the popular reflective bubble covers. As the shipping environment becomes more demanding, moving up the continuum to a quilted solution provides more robust protection. The conclusion: know your product, know the risks throughout your transportation network and thus make an informed decision. Choose wisely!

As the US steadily moves towards stricter GDPs, and Europe and Canada lead the hunt for a tightly knit, overall turnkey solution to cold chain transportation, more than just one solution comes into play. Looking forward, the future of shipping protected product encompasses not only the physical tools we use every day, such as refrigerated equipment and passive thermal protection, but also a mix of less tangible services, such as historical/predictive weather data and lane analysis on the planning side, or the re-use and reclamation of thermal blankets and covers, utilizing asset tracking and reverse logistics in order to increase ROI and moderate capital expenditure.

For a more in-depth look at how passive thermal solutions can be a part of your successful supply chain management efforts, take a look at PDA (Parenteral Drug Association) Technical Report No. 72, Passive Thermal Protection Systems for Global Distribution: Qualification and Operational Guidance, co-authored by Peter Mirabella, vice president of technical services at QPS. [2]

1. Thermal blankets find a growing cold chain role Pharmaceutical Commerce, March/April 2017, p. 28. 

http://www.pharmaceuticalcommerce.com/supply-chain-logistics/thermal-blankets-find-growing-cold-chain-role/

2. PDA Technical Report No. 72, available for purchase at 

Tony Dellumo is sales and marketing coordinator, QProducts & Services, where he manages marketing efforts and inside sales support. He has a BA in marketing and media management from Columbia College Chicago.

An inside look at selection and implementation of passive thermal protection

Big Pharma requires big help in protecting CRT products

The introduction of new therapies coupled with a sense of entitlement to them continues to generate great interest in earlier access to experimental medicines. Generating real-world evidence from pre-approval access programs could present a win-win situation for all stakeholders involved.

Pre-approval access programs, also known as expanded access (EAP) and compassionate use (CU), are complex and encompass many moving parts. These include ethical concerns such as patient safety and equity of access, manufacturing scale-up, and other resource challenges. Despite FDA efforts to assuage fears, not everyone is convinced that adverse events (AEs) discovered in a sicker, expanded access population will not ultimately impact regulatory approval. So, while these programs have existed for decades, some insist that the existing systems are too slow, are fraught with regulatory red tape, and, through “right to try” legislation, that patients should have the right to get access to any medications they believe will help them (see box).

The intent of the FDA’s Expanded Access (Compassionate Use) regulations and guidance documents is to provide earlier and increased access to experimental treatments to patients with serious diseases, not just to conduct research. Therefore, only minimal safety data collection is currently required. Efficacy and other data can be collected, but does not need to be submitted to FDA.

Legislative requirements contained in the 21st Century Cures Act, along with commitments negotiated between the pharmaceutical industry and FDA, as part of the sixth Prescription Drug User Fee Act (PDUFA VI), defines real-world data (RWD) as data collected outside of a randomized clinical trial (RCT). The legislation requires FDA to develop and implement a framework for application of real-world evidence (RWE) to establish efficacy by 2019. The convergence of these two concepts, pre-approval access and real-world data collection, could represent a “win-win” situation for patients, regulators and companies.

RWE comes from the analysis of real-world data (RWD). This data can include observational studies, registries, retrospective database studies, case reports, administrative and healthcare claims, electronic medical records, and pragmatic trials conducted on a broad patient population in routine clinical practice. This RWD can be generated faster and at a much lower cost than in a randomized clinical trial.

Patients in a pre-approval access program are often more representative of those patients who will likely be some of the first patients to take a new drug once it is approved. Pre-approval access patients, by definition, do not meet the entry criteria for a clinical trial. They frequently have been pre-treated, have more co-morbidities, are more advanced in their disease and are generally in poorer health than those in a clinical trial. RWD collected from those patients in a pre-approval access program, in conjunction with clinical trial data, could add value by:

Creating greater precision and clarity as to the safety and efficacy profile of new products, thus improving the labeling and approved indications of products

Improving the amount and quality of information available to patients and physicians, leading to more informed decisionmaking about new products

Demonstrating benefit: Examination of real-world use of products may accelerate the rate at which products prove their value to patients, providers and payers, supporting reimbursement with real-world evidence (demonstrating benefit)

Better identifying symptomatic toxicities that could have a significant impact on adherence and are a major contributor to treatment discontinuation

Allowing further dose/side effect exploration in conjunction with the drug’s clinical trials before drug approval, leading to better information in labeling about appropriate dose without unduly delaying a drug’s approval

The case is especially compelling for rare conditions that have no effective treatments, as well as in circumstances when a randomized, controlled clinical trial is ethically impossible. It also can apply to more common indications, especially to generate safety data and demonstrate efficacy about supplementary indications.

Additionally, the idea that data from pre-approval access programs can be used to support regulatory decisions is not speculative. The most dramatic example is the FDA’s 2015 approval of Vistogard (uridine triacetate) from Wellstat Therapeutics Corp., based entirely on pre-approval access data on 135 patients. It was approved as an antidote to overdosing and to treat certain severe or life-threatening toxicities from chemotherapy.

FDA continues to seek the answer to the question “How can RWE better support regulatory decisions?” At two workshops in September—convened by the National Academy of Sciences (NAS) and the Duke-Margolis Center for Health Policy at Duke University—FDA leadership, biopharmaceutical executives, payers and providers met to begin to identify the barriers to utilization of RWE in regulatory decisionmaking. They also began to layout a path forward to transition from conceptual approach to practical application.

Utilizing RWE will require collaboration, change and investment from every sector of healthcare stakeholders. Regulators, with collaboration from drug developers and payers, will have to formulate standards for RWD collected on patient health status and/or the delivery of healthcare, from a variety of sources. Biopharma companies will have to obtain or develop the expertise needed to design and implement RWE studies and engage in precompetitive collaborations to define best practices.

The Duke-Margolis meeting generated a white paper, 

A Framework of Regulatory Use of Real-World Evidence

, which stressed that going forward, there is a need for continued engagement with the stakeholder.* This ongoing engagement is needed to identify the key questions FDA needs to answer to facilitate sponsor use of RWD and RWE for regulatory decisions. Ultimately, FDA will need to provide appropriate guidance documents to the biopharmaceutical industry to make it part of the drug development process. Recommendations coming out of the meeting also supported creating demonstration projects to facilitate the development of RWE for regulatory decisions.

Generating RWD from pre-approval access programs, combined with companion registration clinical trials, could create valuable infrastructure for RWE demonstration projects, and at the same time, provide greater, earlier access for patients to experimental medicines—a win-win for all stakeholders concerned.

Jane Reese-Coulbourne is a senior consultant at MK&A (

). Since 1995, MK&A has been a leader in healthcare constituency relations. Our clients include major pharmaceutical and biotech companies, as well as device and diagnostics manufacturers. We focus on establishing and enhancing partnerships between our clients and the diverse patient, consumer and professional groups that influence the success of their products and franchises, and the reputations of their companies.

The desires of sometimes desperate patients for access to experimental medicines are most evident in the success of the Goldwater Institute in passing “right to try” (RTT) legislation in 38 states, along with current federal legislation under consideration. These laws imply that patients can obtain access to any experimental medicine and promote the idea of creating an alternative pathway, allowing patients to get access under any conditions without any FDA oversight. In practice, RTT laws have not to date provided any additional access to patients. The final decision on whether or not to give patient access to a not-yet-approved medication still remains with the sponsor.

The focus of most of the federal legislation has been on finding ways to incentivize manufacturers to agree to provide earlier access to experimental medicines to seriously ill patients. Making use of strong support from the Trump Administration and some members of Congress, supporters of federal RTT legislation have been successful in passing legislation in the Senate, while the House decision is pending. Elements of RTT have also been successfully included in other federal legislation, namely the 21st Century Cures Act and Prescription Drug User Fee Act (PDUFA), as well as in the Final Rule. However, despite all of this legislative work, many key issues have not been resolved, or even addressed, in these laws.

In response to demand for earlier access, FDA has taken several steps to streamline and clarify its policies aimed at reducing “procedural burdens on physicians and patients.” These include clarification of requirements for expanded access for both individual patients and for intermediate and large-scale studies, affirmation of the need for minimal institutional review board (IRB) review of protocols—even in cases of emergency use—and a narrower requirement for adverse event (AE) reporting. Addressing sponsors’ concerns that AE reports could derail development efforts, FDA has stated that FDA reviewers are to interpret safety data in “the context in which the expanded access use was permitted.” The agency has even published data it believes should dispel fears about regulatory risk. FDA continues to try to minimize this regulatory risk as a barrier by further clarifying its position and encouraging manufacturers to create pre-approval access programs.

Pre-approval access and real-world evidence: a win-win proposition

 Fig. 1. Deloitte’s Patient Connect framework links various healthcare stakeholders with patient-care information[/caption]

“Patient support services,” as a business driver of the pharma commercialization, appears to be going in two directions these days: one in the chase for ever-better connection with patients by the pharma industry across the board; the other in deeper and more substantive connectivity in specialty pharmaceutical distribution and dispensing. The two goals are not in conflict, but they have different drivers: in the former case, the goal is to pull in more and more diverse data sets, such as those from social media; in the latter case, the need is to better coordinate activities originating with pharma companies (or their outsourced hub services providers), specialty pharmacies, health systems and physicians.

Now, a collaboration between two organizations: the ConvergeHealth business unit of Deloitte, and the Sonexus specialty-distribution business of Cardinal Health Specialty Solutions, have come together to bring some high-powered IT to the patient support problem in specialty pharmaceuticals. Cardinal Health has licensed (for exclusive use in outsourced hub services) the Patient Connect platform of Deloitte, added its own capabilities to it, and will market the result as the Sonexus ConnectSource platform. (Patient Connect has a variety of clients, including among health systems; ConnectSource will be offered exclusively by Cardinal to its clients for its specialty distribution services.)

“Sonexus has had a powerful IT platform in place for several years,” says Jennifer Fillman, VP and GM, Cardinal Health Specialty Services, “and we were looking to modernize it and to provide an ‘accelerator’ to speed up the overall patient support process. Patient Connect appealed to us because it could substantially cut our internal development time, and after we put it through its paces, it was the clear choice for partnering.”

Information technology platforms are a foundational resource for hub providers. The essence of a hub or patient support system is to bring together, coordinate and track a diverse variety of services necessary when many specialty pharmaceutical products are prescribed. Following a physician’s prescribing a drug to a patient, there is a need for a prior-authorization (PA) form to be filed with the patient’s insurer; then a benefits investigation/verification to line up financial resources. The drug (coming from a specialty pharmacy with its own patient support services) might be administered at specialized infusion centers or other clinics; it might also require pre- and post-testing for side effects. Nurse educators might be dispatched to the patient’s home for follow-up.

Adherence takes on special significance with many chronic-care or extended-regimen drugs, especially the highly expensive ones. The payer wants to ensure that an expensive treatment is being administered correctly, to improve patient condition and minimize future hospitalizations. The pharmacy and, to some degree, the pharma company, do not want abandoned scrips that generate no income for either. The health system is concerned with maintaining high adherence levels to meet federal and commercial-insurer expectations.

Deloitte’s ConvergeHealth business unit has spent the past several years developing a variety of IT platforms, and then performing analytics, per client request, on addressing a number of healthcare quality issues. “The key for hub services, and for patient support generally, is to coordinate activities around the therapy,” says Dave Rosner, a principal at Deloitte Consulting LLP who is managing the ConvergeHealth effort. “Many existing patient support systems have a proprietary design, and limit what data can be collected and analyzed. With Patient Connect, we’re providing an open platform into which other IT solutions can be linked, and offering dashboards and visualization to assist in the management of patient care.”

According to Deloitte, the trend toward improved patient engagement is driven by three key stakeholders:

Patients, increasingly engaged and informed, are requesting health solutions that are coordinated, convenient, customized and accessible. Patients are using digital tools and technology to manage their well-being, and are starting to expect an “Amazon-like” customer experience when interacting with physicians, pharmacists and other healthcare service providers.

Providers are interested in using healthcare data to gain deeper insights into the patient journey and to inform treatment decisions that lead to better outcomes—but accessing the necessary data and analytics is often a challenge.

Pharmaceutical companies also want to understand the patient journey so they can develop effective programs to facilitate access to their products, drive medication adherence, deepen brand loyalty and help improve outcomes. But like providers, pharma companies are often frustrated by an inability to access the insights they need.

Patient Connect (and Cardinal’s version, ConnectSource) are cloud-based systems hosted by Deloitte. Patient Connect is also used by health systems (and there are activities going on to link it with health systems’ electronic health records (EHR) systems. Cardinal has tailored Patient Connect to its specific hub services and generally speaking, specialty pharmaceutical manufacturers who are Sonexus clients will be migrated to the system in the near future. A handful of pharma companies are already using it.

Both Fillman and Rosner see additional advances looming in their respective platforms. At Deloitte, Rosner sees the impact of value-based contracting, where health systems’ or pharma companies’ compensation is based on the outcome of the therapy. At Cardinal, Fillman sees the need to make real-world evidence available, both for quality assurance and for drug development. The opportunity presented by wearable medical devices, whose data can be transmitted to ConnectSource, is also being explored.

New IT platform modernizes the patient support data-gathering process

Deloitte and Cardinal Health team up for patient support services

 Fig. 1. There are many compliance risks in pharma interactions on the patient journey. Credit: Helio[/caption]

In this new age of patient centricity, the focus of the pharmaceutical industry is starting to shift from developing relationships with healthcare providers to establishing services and solutions around the patient. This shift arises from the complexities of disease states and the associated disease management options, as well as increased complications in the approval of treatments by insurers. Companies are beginning to create patient services programs to aid patients in the use of their products by providing educational support and reimbursement services. These services can include the provision of free drug, co-payment cards, or other financial assistance to help with the cost of the prescription drug for individuals, conducting benefits investigations with patients’ insurance companies, or providing educational support in disease management. Additionally, patients are increasingly becoming a valuable source of insight and knowledge as opinion leaders, especially in specialty or rare diseases where there may be limited treatments and options for the affected patient population.

In recent years, pharmaceutical and biopharmaceutical manufacturers have begun receiving more attention and scrutiny from government and public entities regarding various offerings of their patient support services programs. One reason behind the attention to these programs has been the country’s focus on prescription drug pricing. Even Congress is beginning to include components of patient services programs in examining drug pricing and in many of its recent investigations of specific companies. Additional attention to co-payment programs and drug costs have stemmed from the August 2016 Government Accountability Office Report on co-payment coupons, which concluded that coupon programs provided to privately insured patients could impact Medicare Part B Drug spending.

Media articles have also started calling attention to the relationships companies are building with patients. The Washington Post recently investigated the practices of companies that sometimes go beyond providing financial assistance for drugs by offering grants and gifts to patients and that “may mask an effort to create customer loyalty or sell pricier drugs for a rare disease.” [1] Furthermore, Bloomberg Businessweek featured an investigation of one company’s aggressive practices in finding rare patients and directing physicians to prescribe its drug. [2]

Due to the changing landscape of healthcare reform, as well as the increased number of specialty pharmaceutical products, this new attention on patient services compliance is becoming a growing risk that companies must address in order to continue to successfully help patients through their patient services programs.

While there are many business and process considerations related to patient services programs, if not managed or executed correctly, these programs can increase companies’ risk for litigation and investigation (Fig. 1). When looking at their programs, companies must consider the overall patient journey. What activities along the path are subject to risk? Who are the key players that partake in such activities? Who should be performing these activities? Is there a legitimate need to provide these activities to the patient? Can these services be provided to the patient by a pharmaceutical company or its agent?

Companies offer different patient support services based on their specific products and disease state. Support activities can be managed internally or be outsourced to “Hubs” or specialty pharmacies. Hub vendors can provide a centralized approach to ensure manufacturers are connected to patients, healthcare providers and insurance providers, throughout the patient journey from prescription to delivery. Specialty pharmacies are often utilized by manufacturers for the distribution of high cost, high touch and/or high complexity treatments and therapies for complex disease states. Manufacturers often outsource all or portions of their patient services programs to these Hub vendors, as well as specific patient support services to specialty pharmacies.

Without established controls and processes and appropriate training within these patient services activities, companies put themselves at risk for potential violations of various laws and regulations.

 Fig. 2. Percentage of pharma companies that share patient information between functional groups, based on a Helio survey[/caption]

Recent enforcement activity has focused on alleged violations of the Anti-Kickback Statute through the usage of Hubs and specialty pharmacies to increase product utilization. In a survey focused on patient services conducted earlier this year by Helio Health Group across pharmaceutical companies of various sizes, 65% of companies surveyed use Hubs to outsource patient services activities that they may not have the resources to manage internally, such as conducting benefits investigations. Companies are also increasingly using specialty pharmacies for the distribution of high-cost drugs for complex and rare diseases. However, companies providing performance incentives (e.g., patient referrals or higher rebates) to specialty pharmacies based upon refill rates are at risk of violating the Anti-Kickback Statute.

Under the Anti-Kickback Statute, it is a criminal offense for manufacturers to “knowingly and willingly” provide any patient who is fully or partially insured by a Federal healthcare program (i.e., Medicare, Medicaid, Veterans Affairs, Indian Health Services, etc.) with any form of a co-payment assistance. In 2014, the Office of the Inspector General (OIG) issued specific guidance on the topic. [3]

Similarly, specialty pharmacies will also be held responsible for patient programs that are at risk of violating these government statutes. Recently, Walgreens settled for $50 million with the Manhattan US Attorney’s office for marketing its Prescription Savings Club program with “discounts and other monetary incentives” to government beneficiaries and providing its employees bonuses “for each customer they enrolled in the program,” violating the Anti-Kickback Statute. [4]

Furthermore, regulatory authorities have been investigating the relationship between companies and charitable institutions who provide patient assistance programs (PAP). Many manufacturers provide financial donations to charitable institutions who provide financial assistance to patients with specific disease states. These charitable institutions may provide patients insured by Federal healthcare programs with financial assistance, including co-payment assistance, as long as the charitable institution remains independent from the manufacturer in all of its decisions and activities. The OIG has issued guidance on Independent Charity Patient Assistance Programs, including a Specialty Advisory Bulletin, a Supplemental Special Advisory Bulletin, Advisory Opinions and Modified Advisory Opinions, which outline specific requirements of independence for these programs. Companies who provide grants to these charities and then influence the provision of financial support for their products or guide the direction of the charities’ financial provisions may be at risk of violating the Anti-Kickback Statute. Over the past two years, the US Department of Justice (DOJ), led by the US Attorney’s Office of Massachusetts, has issued more than a dozen subpoenas to manufacturers related to their donations to charitable patient assistance programs and this topic has received additional media attention.

Many patient support services include patient educators whose role is to provide the patient with information on the approved use of a company’s product and to educate the patient about the disease state for which the product is approved. In many cases, patient educators are trained nurses or other healthcare providers. However, when acting as an employee or agent of a pharmaceutical company, they are not allowed to provide medical advice to patients under the False Claims Act. Companies who hire patients to function as patient ambassadors or advocates to speak on their behalf are also required to abide by the same requirements. Companies should be diligent to train their patient educators, patient ambassadors, patient advocates, and all other patient services team members on responding to medical questions and inquiries from patients to avoid these potential issues and to understand that their role is not to provide medical advice to the patient.

Companies that provide patient services support to coordinate and assist with patient enrollment tasks must ensure the services provided are not influencing medical decisions or working towards favorable coverage determinations to avoid violating the False Claims Act. The Warner Chilcott 2015 guilty plea to the District of Massachusetts included a $125 million payment to resolve criminal liability and False Claims Act allegations for “manipulating prior authorizations to induce insurance companies to pay for prescriptions of Atelvia® that the insurers may not have otherwise paid for and making unsubstantiated marketing claims for the drug Actonel®.” [5]

In the most recent opioid investigation conducted by Sen. Claire McCaskill's office, the report focused on patient services reimbursement and prior authorizations support from Insys Therapeutics. The report “describes the emphasis Insys Therapeutics put on boosting approvals for its highly addictive fentanyl drug Subsys, even for inappropriate, off-label uses, and details an audio recording in which an Insys sales representative misidentifies herself and uses language designed to circumvent the prior authorization process.” [6]

Health Insurance Portability and Accountability Act (HIPAA) and data privacy

While patient centricity emphasizes the importance of patient information, the lack of firewalls and policies may create risk in patient consent and information sharing. In the same survey, 19% of companies stated that sales representatives have access to patient data or information, and 15% of companies share both patient name and medical history between functional areas within the company. Inappropriate access to protected health information (PHI) may create the risk of violating HIPAA regulations, especially if patient consents do not include the ability to share this data.

Federal Food, Drug, and Cosmetics Act/off-label

Patient educators are often utilized in a patient services program to inform the patient of the on-label or US Food and Drug Administration (FDA) approved use of a company’s product. Companies are at risk of potentially violating the Food, Drug, and Cosmetics Act if the information shared with patients does not adequately cover the safety and efficacy details, and thus does not represent a fair balance of product information. Providing information to patients about usage of a product for an off-label indication, an indication that is not in FDA-required labeling of the product, may also put a company at risk. Interestingly, 20% of the companies surveyed indicated that they do provide patient support services in the form of free drug, reimbursement or co-payment support, and education to patients who are using their products for an unapproved indication. Companies must consider how to balance the risk of providing certain services to patients who are using their drug off-label, and which patient services are appropriate to provide or may cause potential liability for the company. Considerations and risks for off-label patient support services are complex, especially with the new debates around first amendment rights as well as FDA’s recent guidance on the issue. [7,8].

Adverse events identification and reporting

Patient support services also pose additional risks to pharmacovigilance, and the accurate and appropriate capture and reporting of adverse events. Ensuring adverse events and product quality complaints are accurately captured and reported becomes increasingly difficult as more information is shared amongst the patient, caretaker, physician, Hub, specialty pharmacy, or internal patient services team members given the direct relationships and activities with patients. As the number of individuals interacting with patients is increasing with these programs, it is important for companies to remember that the potential number of adverse events and product quality complaints may increase. Proper training on identifying and reporting of adverse events to all employees and vendors who interact with patients may be a key factor in remaining in compliance and reducing risk in this area.

How do companies ensure that their patient services programs provide the optimal value to patients while remaining compliant?

One consideration is to evaluate where the patient services group sits within the organization and the reporting structure. Although 33% of companies surveyed stated that the patient services team has its own dedicated group, 41% stated that the patient services team is located within the Brand/Commercial group. For patient services teams that include patient educators, it may be a potential risk for the patient educators to report into sales without establishing strong controls to ensure nurses are not speaking to patients in a promotional nature.

Another consideration is to examine how patient services team members are interacting with patients and healthcare professionals. Do various team members have call or meeting targets? Are Hub coordinators given company-approved call scripts? Are the call scripts appropriate or should call guides be provided? Which team members can assist patients with reimbursement information and directions? Similar to the controls companies put into place when outsourcing activities to third-party vendors when interacting with healthcare professionals, it is imperative that there are comprehensive and adequate controls in place to mitigate any potential risks between the vendors and the patients. These controls must also be applied to internal team members’ processes and activities.

As the interactions between companies and patients are increasing, access to and sharing of PHI are areas that must be scrutinized. What elements of patient information are being shared with whom, not only within the patient services team but also across various functional areas in the company? Companies may need to consider the implementation of a data privacy management program, enhanced by technical considerations and overall decisions, as well as training components and strict supporting documentation.

Similar to monitoring and auditing programs created to address compliance adherence in their sales force, 59% of companies surveyed stated that they are starting to audit and monitor the activities of various patient services functions, such as patient educators and case managers. Companies are also introducing advanced analytics and technology platforms within programs to proactively manage and avoid compliance risks. They are creating requirements for advanced compliance programs utilizing analytics, and automating audits and reviews of calls utilizing next-generation digital methods, such as voice-to-text technology.

A well-run patient services program that can provide effective disease education and financial support to patients could potentially be lifechanging for many patients. However, with so many patient needs, many unanswered compliance and legal questions, and the increasing scrutiny into this area, companies must ensure their programs are effective for the patients while simultaneously mitigating their ongoing risks.

https://www.washingtonpost.com/news/wonk/wp/2016/06/14/how-drug-companies-use-gifts-and-internships-to-buddy-up-to-their-most-valuable-patients

https://www.bloomberg.com/news/features/2017-05-24/when-the-patient-is-a-gold-mine-the-trouble-with-rare-disease-drugs

The OIG guidance states “Pharmaceutical manufacturers offer copayment coupons to insured patients to reduce or eliminate the cost of their out-of-pocket copayments for specific brand-name drugs. These coupons constitute remuneration offered to consumers to induce the purchase of specific items” (

https://oig.hhs.gov/fraud/docs/alertsandbulletins/2014/SAB_Copayment_Coupons.pdf

https://www.justice.gov/usao-sdny/pr/manhattan-us-attorney-announces-50-million-settlement-walgreens-paying-kickbacks-induce

https://www.justice.gov/opa/pr/warner-chilcott-agrees-plead-guilty-felony-health-care-fraud-scheme-and-pay-125-million

https://www.mccaskill.senate.gov/media-center/news-releases/breaking-mccaskill-opioid-investigation-releases-first-report-detailing-systemic-manipulation-of-prior-authorization-process-by-insys-therapeutics-

U.S. Department of Health and Human Services Food & Drug Administration (FDA) January 2017 memo Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products 

http://www.ascrs.org/sites/default/files/FDA_Memorandum--Public_Health_Interests_and_First_Amendment_Considerations_Related_to_Manufacturer_Communications_Regarding_Unapproved_Uses_of_Approved_or_Cleared_Medical_Products_Jan_2017%20%281%29.pdf

FDA’s January 2017 Draft Guidance Medical Product Communications That Are Consistent With the FDA-Required Labeling — Questions and Answers

Marci Juneau is a partner at Helio Health Group and is based out of Atlanta, GA. Prior to Helio, Marci was director at Huron Consulting Group’s Life Sciences Practice and worked for Ernst & Young’s Fraud, Investigation and Dispute Services, focusing on healthcare. Marci has an MBA from Georgia Institute of Technology and a BS in Engineering Science and Economics from Vanderbilt University.

Minna Bak is a senior manager at Helio Health Group and is based out of the New York, NY office. Prior to Helio, Minna worked at Acquis Consulting Group and Huron Consulting Group’s Life Sciences Practice. Minna has an MBA from New York University and a BS in Bioengineering from the University of Pennsylvania.

A look into the growing compliance risks associated with patient services

First physicians, now patients: Risk avoidance in patient support programs

When it comes to the business of pharmaceuticals, it’s the sales team that keeps the ship afloat.

And that, in turn, makes the vehicles that take them out on sales calls to maintain and build client relationships a vital part of any pharmaceutical company’s operation.

If you were to add up all of the pharmaceutical sales fleet vehicles in the world, they would total approximately 300,000—140,000 in North America alone. On average, that’s 700 vehicles per company. But, when you’re only looking at the largest 15 companies, that figure skyrockets to an average of 5,000 vehicles dedicated to ensuring a sales team is on the road doing its job.

Knowing these figures, it’s no wonder that a pharma fleet can rank among a company’s top expenses when you look at the combined cost of the vehicles, maintenance, fuel and repairs. Fuel contributes significantly to the overall cost of running a fleet—as much as 60% of the total operating costs in some cases—but the price of fuel is only part of the equation. Often, the behavior of a fleet’s drivers—things like harsh braking, speeding—contributes to unnecessarily driving up this expense. Another significant expense is depreciation, which can make up as much as 62% of fixed costs (depreciation, lease or financing expense, insurance). This too can be managed, however, if a company adopts a strategic approach to acquisition and the cycling of vehicles.

In pharma, as in most industries, the historical perspective of managing a fleet this large has been that it’s a necessary cost of doing business. A company needs these vehicles to bring in income, so traditionally they were leased or purchased and maintained but not necessarily according to a larger strategic plan designed to maximize ROI.

Sales vehicles have become a vital tool in recruiting top talent. And that means older cars in the fleet hold less value to a company, since they won’t help woo an experienced sales rep from another company.

In an analysis of the fleets of its top six pharmaceutical clients, ARI, an international fleet management company based in Mt. Laurel, NJ, revealed that two-thirds of them offered different trim levels or even higher end vehicles to sales managers vs. reps. Half of these companies fill their fleets with a single manufacturer, the most popular of which is Ford (with Escapes, Fusions and Edges as the most prominent models).

When a pharma company recognizes that the costs associated with its fleet can be minimized by tracking the data produced by its vehicles and drivers, the company’s bottom line benefits.

Though some companies might consider the option of managing their own fleet, hiring an outside fleet management company has its benefits. These experts can support every aspect of a fleet throughout the entire life cycle of a vehicle:

These firms can also offer services related to a company’s driver, too, including:

And in addition to all of these tools and resources, a company like ARI brings to the table real on-the-ground experience and results from businesses all over the world across a wide span of industries. A good fleet management company won’t simply follow orders or crunch data points, but work as a partner and consultant, offering knowledge derived from the real world. An outside partner with a broad database of industry knowledge is able to benchmark a fleet to ensure that it’s working at least as well as or—optimally—better than the industry standard.

ARI’s survey of six key pharma clients to evaluate vehicle ordering trends and develop best practice recommendations based on the data revealed some trends, which supported several universal recommendations:

Working with a single manufacturer. If it is possible, partnering with a single OEM can streamline the process and uncover efficiencies that are likely to lead to savings.

Offering multiple selector levels. Distinguishing among trim levels based on a person’s position (i.e. rep versus manager) can help an organization more closely manage costs.

Managing costs by evaluating geographic needs. Not every driver may need 4WD or snow tires; only those who will be working in the Snow Belt region need those features.

Allowing for driver-paid options. Companies can make a vehicle more attractive to a driver if they allow certain higher-end options, such as leather or heated seats, or a sunroof to be added at the employee’s expense.

Partnering with a fleet management company like ARI can help companies understand not just their own fleet, but also the larger industry trends that can help your organization drive costs down, and efficiencies and employee satisfaction up.

Modern vehicles generate hundreds of data points that can be analyzed in an effort to uncover inefficient processes and control costs. But just having the data doesn’t mean the fleet will find the answers that will produce efficiencies and savings—or even identify problems before they happen.

It’s important to know which vehicles are costing you the most, but it is just as critical to understand why those vehicles are costing you the most. The insight that a comprehensive Big Data strategy provides enables an organization to perform predictive analysis. This empowers businesses to determine not only which units broke down, but ultimately, which units will breakdown. It also enables them to see which drivers may be adopting poor behaviors behind the wheel, and take action through training and counseling before an accident ever occurs.

As a consultant, ARI can help a company determine the most efficient size of a fleet based on a business’s needs and goals. They can help decide when to replace aging vehicles and identify those that aren’t being used efficiently. They can uncover ways to improve fuel economy. And they can help implement programs that lead to safer drivers and fewer accidents.

So how does all of this play out on the ground?

Take a recent case of a global pharmaceutical company that was faced with a noted increase in accidents caused by distracted driving. In 2013, the company partnered with ARI to map out a comprehensive safety strategy that included a set of six core training programs and additional training for drivers who were subsequently involved in an accident after that training, with the additional training specifically targeted to address the cause of the incident. In 2016, they automated the training program, so every new driver was required to take the core training modules and approve the company to complete a motor vehicle report (MVR) check.

Since the automation of the program, the company has experienced a 22% drop in the total number of accidents and a 22% drop in accident costs as well. What does that mean for their budget? In 2016, the company’s total claim spend was $221,081 with a total of 75 accidents; as of May 2017, its current claims spend is $69,147 with a total of 26 accidents.

More and more pharmaceutical companies are realizing the bottom line benefits of a well-managed fleet to support a sales team, and are looking to outsource this work to companies with the knowledge and experience to maximize the return on investment and reduce the total cost of ownership of every vehicle they own.

Braden Pastalaniec is manager, Strategic Accounts, for ARI, an international fleet management company based in New Jersey that works with companies in a variety of industries—including pharmaceuticals—around the world, managing approximately 1.5 million vehicles. Visit ARIfleet.com.

Managing pharma auto fleets

AmerisourceBergen, No. 11 on the Fortune 500, is one of the Big Three drug wholesalers in the US, and positions itself as a provider of “innovative partnerships with global manufacturers, providers and pharmacies to improve product access and efficiency throughout the healthcare supply chain.” It was one of the earliest major wholesalers to invest in specialty products and services, and now has operations outside the US as well. In 2013, it struck a pioneering, 10-year deal with what was then Walgreens (soon to become Walgreens Boots Alliance) to set up a global drug-sourcing business. And in 2012, it acquired World Courier, a relatively small acquisition (in the scheme of behemoth drug-distributor affairs), but one that puts it squarely in the business of supporting pharma clinical research.

More recently, it acquired (2015) it acquired MWI Veterinary, then a leading animal health distributor, and that brought Jim Cleary, MWI’s president, into the company. This year, following an internal reorganization, Jim Cleary was appointed head of the Global Commercialization Services & Animal Health unit (the other half of the company is now known as Pharmaceutical Distribution and Global Sourcing).

 sat down with Jim Cleary to find out what’s happening internally at AmerisourceBergen; here’s what he had to say.

1) First off, ABC has recently announced some new organizational structures, one of which puts you as head of the Global Commercialization Services & Animal Health business unit. Tell us about this new structure.

We recently approached and announced a new operating model that better aligns our organization—of 20,000 associates—to the shifting healthcare marketplace, our customers’ needs and improved patient access. As part of this transformation, AmerisourceBergen’s customer-facing offerings are now aligned under two groups: Pharmaceutical Distribution and Strategic Global Sourcing; and Global Commercialization Services and Animal Health. By simplifying and enhancing our operational structure, we’ve been able to approach customers in a more consolidated fashion, identify greater connectivity between businesses and enhance processes that make it easier for our customers to do business with AmerisourceBergen.

With this transition also came some immediate changes even for me as I was asked to take on an expanded role and lead the Global Commercialization and Animal Health group. It’s safe to say I was honored to be considered for this position, and incredibly excited to leverage my 20-year career in animal health, using this as an opportunity to deepen my learning on the human side—ultimately creating a more cohesive and unified experience for our customers.

As part of my current role within AmerisourceBergen, I oversee the company’s commercialization services and animal health businesses, as well as international development. Within our product commercialization services specifically, there are a number of businesses units that support this work including, World Courier, ICS, Lash Group, CenterX, Premier Source, Xcenda, Innomar Strategies and Profarma Specialty.

Pharma commercialization, these days, means a lot of activities around patient support services,

 particularly for specialty pharmaceuticals. How is ABC executing on this driver?

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