Nicholas Basta, Editor Emeritus

More details have emerged from an announcement last January that Cell Matters SA is partnering with Cryoport, a leading vendor of supply chain services for the emerging field of ultra-low temperature-controlled shipping and storage of cellular and gene technologies (CGTs). Cell Matters, based in Liege, Belgium, is addressing a critical step in CGT research and commercialization: the points where biomaterials are gathered from patients or donors, packaged (typically into “leukopaks,” which are bags containing a filtered, concentrated volume of cells) and then shipped to a manufacturing facility or lab. “Our goal is to de-risk these supply chain steps,” says Delphine Connan, CEO of the company.

Cell Matters is about to gain regulatory clearance for its Liege facility to cryogenically refrigerate leukopaks. Two facilities are in the works in the US, in Houston and in New Jersey, and are co-located with Cryoport, which itself has just opened two new regional logistics centers in Houston, Texas and Morris Plains, NJ. All three facilities are expected to be up and running by 2024 or sooner, says Connan.

As things stand today, there is only rudimentary standardization in the leukopak cryopreservation step: some CGT Companies seek to ship the Leukopaks, from the collection center, without cryopreservation, expecting that they will reach their destination within 48 hours maximum, after which cell viability declines. Currently, when the leukopaks are cryopreserved, the methods to do so vary, and can create quality problems. Cell Matters offers to cryopreserve leukopaks in less than 24 hours within the region of their collection centers, cryopreserve them via standardized processes, and store or ship them to meet tight manufacturing timelines (when CGT clinical and commercial products are involved). Thus, Cell Matters offers expertise in cryobiology, cell therapy production, and, together with Cryoport, bio-logistics.

For its part, Cryoport offers global logistics services for CGT materials, making use of its proprietary, dry vapor liquid-nitrogen containers (as well as for shipments at warmer temperatures). “The strategic alliances we are forming, coupled with select acquisitions in services and products, are strengthening our comprehensive supply chain solutions for the life sciences and our capacity to serve the industry’s evolving and growing needs,” said Jerrell Shelton, Cryoport CEO, at the time of the January announcement.

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Companies hope to combine their cryogenic expertise with dedicated packaging and supply chain services

Cryoport and Cell Matters to Collaborate on Standardizing Cell Therapy Supply Chain processes

Over the past year—and in the face of a pandemic that has snarled supply chains and work schedules—the US pharma industry has made measurable progress in its march to the November 2023 deadline for compliance with the Drug Supply Chain Security Act (DSCSA). DSCSA, passed in 2013, set out a 10-year process for creating “interoperable, electronic tracing of products at the package level to identify and trace certain prescription drugs as they are distributed in the United States.” Although both industry and FDA have marked some key steps, there is a lot yet to be done, and not all of the pharma supply chain (from manufacturers to dispensing pharmacies and hospitals, with distributors and contractors in between) is moving at the same pace.

In the past 12 months, FDA issued a batch of guidance documents that detailed its view of product verification processes (clarifying what a “suspect” product is) and procedures for handling product returns that are salable. One guidance, “Enhanced Drug Distribution Security at the Package Level,” however, elicited a sharp reaction from the Healthcare Distribution Alliance (HDA), which said that the document should be withdrawn since it proposes a system that 

“does not exist, cannot be built by 2023, and poses unacceptable security and compliance risks.”

HDA objected, among other things, to the recommendation that a trading partner, FDA, or a state official, could get a rapid response to trace a suspect product with one request; HDA suggests that because the data of such transactions are stored across multiple databases, that quick response is not possible. FDA has been quiet about revising or withdrawing the guidance.

Another key guidance, issued early this year, was the long-awaited proposal for managing the licensure of drug wholesalers and third-party logistics providers (3PLs) by FDA—superseding the many state-level procedures already in place. This guidance represents the first time that FDA officially will oversee wholesaler and 3PL activities, and will be issuing operating licenses and inspecting facilities going forward. (At press time, the comment period on this guidance was still open.)

On the industry-collaboration front, there are at least three significant activities going on: the Partnership for DSCSA Governance (PDG); the Open Credentialing Initiative (OCI), and HDA’s ongoing surveying and codifying of industry practices and readiness. None of these organizations has force of law or regulation, but all of them, one way or another, are trying to establish agreed-on industry practices to make both interoperability and understandable data file transfers happen.

In early 2022, HDA published an updated Guidelines for Barcoding, superseding pre-DSCSA guidance and essentially defining what the barcodes will look like for fast data collection at distribution centers. The organization is also surveying its members (most recently, to determine how extensively the electronic product code information services, or EPCIS standard for electronic communication, is being adopted) and providing feedback to FDA on its guidances. In the recent past, HDA took a leadership role in establishing the concept of a “verification router service” (VRS), which will serve as a phone book for how queries on product identifiers will be directed from the query source to the information source.

Partnership for DSCSA Governance (PDG), set up intentionally to bring together manufacturers, wholesalers, and dispensers to represent the full breadth of the supply chain, issued the first chapter of a “Foundational Blueprint for 2023 Interoperability” last year. The document is fairly technical and detailed around file descriptions; the next step is to take the output of four working groups to set up how connections will be made between trading partners. The working groups are Credentialing and User Authentication; Serialized TI/TS Data Exchange; Verification Architecture; and Tracing Architecture.

OCI is organized by the Center for Supply Chain Studies, a Pennsylvania nonprofit, and skews toward software vendors of blockchain-related technology (see OCI’s 

 on interoperable electronic credentialing). So far, it has published several proof-of-concept projects that demonstrate how the technology could function.

“It’s pretty clear that there will not be one communication technique, or one software application, that will connect all trading partners to each other,” says Perry Fri, EVP, industry relations, at HDA. “Industry standards will help.”

“Manufacturers have one answer to interoperability, and wholesalers have another,” notes Greg Cathcart, president of Excellis Health Solutions. He agrees that “multiple systems and standards will be written,” but that “the ultimate question is, ‘Who owns the data?’”

), generally regarded as the most widely used IT system for DSCSA compliance, has gone in a direction of creating a network of trading partners across the supply chain, and setting up communication processes within that network for connectivity. There will always be outsiders to the network, or special cases, though, and so Shabbir Dahod, CEO of the company, says that the Opus platform, the company’s newly announced software version, will be set up to provide interfaces to other software tools. “Other companies have already layered applications on Opus, and we can support that,” says Dahod.

The solution provider landscape has changed in recent years. Most notably, Antares Vision, an Italian provider of packaging line equipment and software, has acquired rfXcel, Tradeticity (a Croatian traceability software vendor), Acsis, a software provider oriented toward warehouse management, and the assets of Adents, a French firm. Systech, an early innovator in packaging serialization, was acquired by Dover Industries and linked to the Dover subsidiary Markem-Imaje, a marking/labeling firm. Movilitas, a European consulting and systems integration firm, has been acquired by Engineering Group, a global IT provider; similarly, Excellis Health Solutions, based in the US, is now owned by NNIT, a Danish IT firm.

According to industry sources, the great majority of manufacturers are now routinely barcoding their products with unique serial numbers (this was an early DSCSA milestone). Packaging vendors benefited from the business driven by that requirement. However, those numbers are not being routinely shared and verified up and down the supply chain—that requirement has been delayed to 2023. A key element of serial code transmission is aggregation—the ability to infer what codes are inside a case of product (which might have dozens or hundreds of individual units), from the “parent-child” relationship established by the packager when the case was composed.

Lacking aggregation, wholesalers and distributors will be compelled to break down pallets and open cases, and perform a manual serial code check.

FDA’s 2022 proposed guidance, for the first time, explicitly permits inference from aggregated cases; however, this puts the onus on the packager to collect the unit data to create the parent-child relations. “While essentially everything we receive is barcoded, only half of it, at best, is aggregated,” comments Pat McGinn, SVP of supply chain integration at Eversana, a 3PL and commercial-services provider to life sciences. “While the aggregation levels are improving, it’s a problem, especially for generic manufacturers.”

McGinn has some good advice for industry supply chain managers, regardless of how rapidly they’re aggregating: pay close attention to how your products enter the supply chain, and where it’s best to compose larger or smaller aggregated containers. An example of this is the use of inner packs—the bundles of product (say, four bundles of 12 in a case of 48); if used, these need to be aggregated as well. But it’s conceivable that the packager might do better with shipping cases of 12 rather than 48. “You might spend a little more on the packaging, but you could save substantially on service requirements or product damage across the supply chain,” he says. Eversana offers to consult with its clients in this matter.

Back on the software side of the DSCSA compliance march, there is some industry buzz around a recent product offering of LSPediA, which provides serialization and supply chain software. When fully implemented, DSCSA will require the documentation of a shipment (in digital form) actually match up with the physical shipment; ideally, the documentation arrives prior to the shipment, and then the receiver verifies the identity of the two. But errors are rampant in both the documentation (where an errant “0” or hyphen could throw off an identification field) and in the physical shipments, where a nominal case of 48 might have 47—or 49—units.

LSPediA has introduced the Investigator application, a tool that automatically (and with some programmed intelligence) goes through an EPCIS or similar file and identifies errors in the documentation. Without such an automated tool, the checking needs to be performed manually. According to Michael Ventura, a VP at the firm, some companies have spent hours looking for an error, which Investigator found in minutes. In recent months, both AmerisourceBergen and Cardinal Health—which together represents roughly two-thirds of primary distribution of pharmaceuticals in the US—have adopted Investigator, as well as numerous small distributors and some manufacturers.

One unexpected outcome of the COVID-19 pandemic is the intense focus, these days, on supply chain practices and problems (think of how the suppliers of baby formula are currently dealing with that issue). “We don’t have to explain to outsiders what the importance of supply chains is anymore,” notes HDA’s Fri. For all the disputes for and against the value of DSCSA in its early days, the industry is benefiting from the new capabilities that serialization and traceability are beginning to provide to the industry.

TraceLink’s Dahod says that traceability is foundational to what the industry will be able to accomplish going forward. An example of this is a newly announced capability to predict product shortages in TraceLink’s Opus platform. The company claims that shortages can be predicted 90 days out, with 80% accuracy. Similar supply chain improvements are expected from a newly announced partnership between TraceLink and Kinaxis, a company that specializes in supply chain and logistics analytics and optimization.

Other companies have adapted traceability to specialized applications: rfXcel, for example, demonstrated the utility of tracking cold chain shipments via its software (cold chain products need to have documentation of the temperature and environmental conditions of the shipment, when the shipment arrives).

And then there is anti-counterfeiting, which, from a legislative perspective, was the driving force to DSCSA passage in 2013. Although most US observers note that counterfeit product is at worst a minor factor in US distribution, there have been some recent, startling instances. The worst example, arguably, was 

 that some $250 million worth of its HIV and other products was allegedly diverted or counterfeited in the past two years. Gilead brought civil suits against a wholesaler and pharmacy ring that crossed 10 states. The US Dept. of Justice is reportedly now looking into the matter.

While DSCSA barcodes figured in the Gilead and other counterfeiting discoveries recently, industry experts agree that the serial codes alone won’t be unbeatable countermeasures. The use of authentication technologies—holograms, security inks, microprinting, and the like—will also figure. A few vendors working in the DSCSA environment, notably Systech and Covectra, are offering authentication technologies that use the same label as where the serial codes are printed.

Recently, Covectra updated its previously announced StellaGuard technology, which enables an investigator (or, a consumer) to use a smartphone camera and internet connection to verify a label, based on the precise positioning of star-shaped particles in the label (the positioning is unique to each unique serial code).

Systech is promoting its e-Fingerprint technology, which uses a similar logic based on the fine details (flaws) in a printed label. Both technologies depend on accessing a database of the labels’ original features that the smartphone compares; both have the utility of enabling consumers to do their own, on-the-spot authentication.

Yet another direction being taken in the traceability path (but not necessarily DSCSA-compliance-driven) is the use of radio-frequency identification (RFID) labels in addition to the 2D barcodes. RFID scanners in place at a hospital pharmacy can be integrated into an inventory- and security-management process, as well as to ensure the right medication is being received by the right patient. Kit Check has been a pioneering firm in this effort, and there is now an industry group, the DoseID Consortium, that brings together the labeling service providers and suppliers of RFID technology. Last fall, ears perked up when AmerisourceBergen announced it would offer RFID labeling for medication trays (which hold multiple doses of medicines) used in hospitals.

These new applications are not only instances of how technologies can find places in niches of the overall pharma supply chain, but also how technology has continued to move on over the near decade that DSCSA has been in place. Nevertheless, the DSCSA mandate is in place for all parties in the pharma supply chain, and time is running short. “Manufacturers need to be working now on finalizing their connections with their wholesalers,” says Fri. “Next year, those wholesalers will be busy getting aligned with the downstream pharmacies and hospitals, who have big hurdles to get over.” To that end, HDA is generating content and pooling together resources for the pharmacy community on its website, 

The clock is ticking on a massive effort to bring interoperable, electronic tracking of pharma shipments in the US

Countdown to 2023 DSCSA Compliance

Industry-sponsored patient support programs have become an essential “lubricant” for coordinating care of patients with complex medical needs. By bringing together the drug developer with the healthcare providers (HCPs) and the payer network, therapies can get to patients sooner, with better overall results for all. Especially with complex specialty pharmaceuticals. And most especially for the fast-growing field of rare or orphan diseases.

That being said, patient support programs, or hubs, remain an underutilized part of healthcare. A 2020 survey from Accenture found that only 18% of patients are aware of the programs being offered—a number essentially unchanged from 2015, when an earlier survey was performed. This is despite indications that industry is funneling more funding into the programs.

There are two basic problems that account for this lack of uptake, according to Anthony Romito, life sciences lead at Accenture. One is organizational issues inside pharma companies that limit how well the organizations promote their services; another is the lack of communication to HCPs of the value of patient support.

On the organizational side, “Most organizations’ hubs are either outsourced and operated by a third party, or they sit in med affairs or market access” departments, he says. “For brand teams, these organizations are not necessarily knitted into the DNA of their go-to-market strategies; there are big gaps despite increased investment.”

Equally problematic, “Pharma companies have generally done a poor job of measuring the clinical effectiveness of patient-support programs, and so HCPs have been reticent to recommend them to their patients.” However, Romito sees some progress here: demonstrating values like reducing time to first dose, or improvement in patients staying on therapy, enable the pharma companies to demonstrate value to the HCPs.

Romito cites the variety of support programs sponsored by AbbVie for its blockbusting Humira treatment (currently the most valuable drug in the world, with sales of $20.7 billion) as an industry pacesetter. “AbbVie has been diligent in demonstrating longer-term patient retention and better outcomes through its support programs,” he says. The equation is simple: provide the service, measure the outcome, and communicate to HCPs.

Even so, industry appears to be moving in the opposite direction when it comes to close coordination of patient-support services and product management. Helio Health Group, a consulting firm, has surveyed the field for five years running; its 2021 survey, published in December, showed that, when a patient-support program exists inside a pharma company, it was placed within the brand/commercial team at 37% of pharma companies in 2017—but only 8% were so situated in 2021. (Conversely, there was growth in placement in managed markets teams, and dedicated patient-service teams.) A major reason for this decline is the difficulty in maintaining a compliant program, avoiding such federal restrictions on patient-data access, or providing improper financial inducements to patients.

The ”classic” (circa five to 10 years ago) hub program was focused on moving patients through the obstacle course of paperwork for getting a prescription and getting it reimbursed. The process often starts with a benefit verification (BV) process to determine insurers’ policy on a drug or therapy. Payers’ use of prior authorization (PA) procedures require physicians to complete sometimes complex diagnostic evaluations, and symptom descriptions. Payers can also require so-called step edits that call for trying a variety of other treatments (usually, the less expensive ones) before the physicians’ preferred choice is permitted.

All these complexities are magnified for many rare diseases which, as Jan Nielsen, division president for patient support solutions at AssistRx, says, can take upwards of six to nine years to correctly diagnose. Testing that might originate with a patient’s primary care physician can itself require a fight with an insurance program’s benefit structure.

For the most part, patient-support providers have built information technology (IT) tools and databases to handle the paperwork, so now there are eBV and ePA resources to be used either by physicians or by the hub providers to assist physicians’ offices. Similar programs are in place for copay analysis and availability, and in some cases, patient assistance programs sponsored by manufacturers. (These have their own requirements for financial disclosures, and might have only limited durations during the patient journey.)

So-called “hub-light” programs pretty much start and stop with these digital services (perhaps with some in-person call- center activity included). But for complex pharmaceuticals, and especially for the newly establishing field of cell and gene therapies (CGTs), many more services are wrapped around the prescription. “There are between 5,700 to 6,000 preclinical and clinical assets that are being developed globally in terms of CAR-T and inclusive of gene therapies,” says Maria Kirsch, GM and head of patient services at Eversana. “This will be a massive wave of the most powerful therapeutic modality in the history of our industry that will address some of the most severe unmet needs for cancer patients, rare disease patients, and other patients who are, unfortunately, on their last hope of treatment, as they have failed other treatments.

“Taking that a step further,” she adds, “We estimate approximately 900 assets are in clinical-stage development. There is a higher likelihood of clinical trial success, for example, with Phase III, CAR-T programs, so hundreds of new CAR-Ts or cell therapies coming into the market will help patients’ lives, but make no mistake, there will be major implications and a significant amount of overhaul to our healthcare systems globally, to be able to absorb the clinical impact, operational impact, and financial impact of these therapies.”

Eversana supports seven exclusive rare disease products, according to Kirsch, “all with patient-service offerings being a critical component.” For companies like Eversana and others, patient support in rare diseases often involves coordination with family caregivers, in addition to the interactions with providers and payers. An estimated 60% of patients with rare diseases are under the age of 18, and a high proportion of such diseases involve chronic care. “We are often working with parents or caregivers to coordinate therapy, schedule adherence plans, and coordinate life coaching for major life events like starting school, going to college, or starting a family,” says Kirsch. “Through education and close connections with patients, we are able to anticipate challenges they may have, such as dietary restrictions, and provide them with the skills to overcome them.”

By contrast, the appeal of many of the CGTs—commercial or in clinical-stage—involve what amounts to a “one-and-done” procedure (at least, this is the promise of many of them). Once a patient’s cells have been collected, manipulated at a cellular or genetic level, and reinfused, the potential for a near-complete cure of a cancer or birth defect is high. Getting the patient to that point, however, can require travel accommodations (since many of these therapies are available only at selected medical centers), multiple trips, and—most significantly—long-term follow-up to ensure that the therapy is permanent.

“Give credit to Novartis for getting an OIG (Office of Inspector General of HHS) ruling that allowed low-income Kymriah patients to have their travel and related services legally reimbursed,” says AssistRx’s Nielsen. This occurred in early 2021; Kymriah, one of the first commercial CGTs, nominally costs $475,000 per patient. For support programs like these, AssistRx enables patients to be quickly reimbursed via e-banking services like Zelle or PayPal.

Mention of the HHS OIG highlights the line patient support providers must constantly adhere to, because poorly monitored practices can lead to serious HHS violations. Helio Health, which runs the aforementioned survey, notes that manufacturers have been increasing their oversight of nurse educator practices and awareness of patient privacy requirements, while reducing their support of some patient assistance programs (which provide direct financial support). Caution is the watchword.

It’s hard to say whether the pharma industry’s emphasis on CGTs is influencing patient-support providers to get into clinical trial engagement, or whether those providers’ growing expertise is being better appreciated by clinical trial managers, but the upshot is that there is substantial value in providing patient support during trials, and business is growing for those providers. This trend has also been boosted by the pandemic, which drove many clinical trials into a decentralized, remote-services version.

“Over the past 18 months, we’ve become engaged in about a half-dozen programs,” says Nielsen. The main driver is trial patient retention. “Especially for some rare diseases with limited trial populations, the need to keep patients in the trial is critical,” she adds. “Service providers like us provide adherence nurse educators, helping remote patients with complex diagnostics and drug-delivery devices, or complicated drug regimens. We’ve become the 24/7 hotline for trial patients.”

In a February announcement, Eversana debuted a data-driven service for clinical researchers by partnering with Thread, a provider of decentralized clinical trial management and clinical outcome assessments (eCOA). The company will combine its commercial capabilities in linking real-world data and electronic health record (EHR) data with Thread’s, thus enabling “continuous active, passive, retrospective, and prospective data collection with patient consent and identity security as central tenets,” according to Eversana. Another Eversana partner, Datavant, provides patient privacy and security.

“In the evolving world of real-world data, registries, and clinical trials, it has become increasingly likely that a patient could end up participating in all three through the course of their care journey,” says Eversana’s Kirsch.

The clinical-to-commercial spectrum could have important benefits for winning over HCPs by the time a drug is approved. Accenture’s Romito says that the ideal entry point for getting patient-support programs engaged is in Phase II of a drug trial. “Today we have long lag between measuring the clinical value of the drug and the impact of the patient support service,” she notes. “There are untapped opportunities to have collaboration between the clinical development team and the commercial development team. We’re seeing more of this in the CGT space, with less walls between two organizations.”

There are unplumbed opportunities in bringing advanced digital technologies, some of them cloud-based and utilizing artificial intelligence, to better serve patients and the clinical research organizations driving for drug approvals or for payer acceptance. Accenture has rolled prior work in digitizing patient services into a broader, cloud-based platform it calls Intient. Eversana has a “next-generation” patient-services platform called Actis Patient Relationship Management, which promises to use predictive analytics and behavioral science to improve the patient experience.

Another approach is from AiCure, which offers expertise in what it calls “digital biomarkers” of patient condition. It started out being able to confirm a patient taking a clinical trial drug dose by having the patient do a video recording of the act with the patient’s smartphone. More recently, it has developed methods to observe patient condition for diseases such as Parkinson’s to assess whether in-person intervention is needed. While the technology has been used mostly during clinical trials, “We are in discussions with patient support-groups to engage with them,” says Rich Christie, MD, PhD, chief medical officer of AiCure. Most recently, it has partnered with Science 37, a clinical trial IT provider, to monitor patient condition for those suffering from depression.

Yet another approach is being championed by BrightInsight, which offers a compliant, cloud-based platform with which to combine apps, devices, companion diagnostics, and other resources for remote patient support. A showcase example is a partnership with CSL Behring for the latter’s Hizentra (immune globulin subcutaneous) drug, used for the rare diseases primary immune deficiency or chronic inflammatory demyelinating polyneuropathy. These serious conditions require patients to self-administer Hizentra multiple times daily. The BrightInsight platform enables CSL Behring to provide a smartphone app to manage infusions, get reminders, and record and share their infusion journal with their doctor.

Biopharma sponsorship of patient-support programs and treatments for rare diseases is growing, but gaps remain 

The Pulse of Rare Disease Support

 a newly released federal court document details an 18-month investigation and enforcement action by Gilead Sciences against a group of wholesalers and pharmacies allegedly engaged in an elaborate ring that crossed the US-Canada border and involved actors in 10 states. In most cases, authentic bottles of Gilead drugs branded as Biktarvy and Descovy were emptied and filled with other products including, dangerously, Seroquel (quetiapine, now divested from originator AstraZeneca), a powerful antipsychotic. Several wholesalers were involved in the scheme, according to the court filing, and multiple pharmacies purchased the fake products and dispensed them to patients between August 2020 and this year. Gilead issued a warning

 last August about the fake products and by then, most of the fakes had been seized under the Lanham Act, which allows brand owners to seize counterfeits prior to resolving legal actions.

More than 85,000 bottles were seized. According to press reports and online sources, Biktarvy retails for around $3,500 per bottle (a 30-day supply) and Descovy, $2,000. Together, the drugs represent over $10 billion in annual sales for Gilead, which has also stated the nominal value of the fakes was $250 million.

The court filing (Case No. 21-cv-04106-AMD-RER, filed in the Eastern District of New York) makes for shocking reading. According to Gilead, the counterfeiting ring involved what it calls “leader defendants” who orchestrated the sourcing, delivery and sale of the fakes; “distributor” and “supplier” defendants, who supplied the drugs; and “marketing” defendants, who solicited sales to pharmacies. Several of the distributors or suppliers are called “fly-by-night” companies, incorporated in the past couple years in various states, and some of whom operated from their homes. The court filing names 74 individuals and organizations, across 10 states.

Gilead states that the defendants created the fakes in a well-known counterfeiters’ practice: “The original foil on the bottles had been stripped away, the authentic medication removed and replaced with foreign medication, and then a replica of the tamper-evident seal was used to re-seal the bottle. Traces of the original tamperproof seal remained in the grooves of the counterfeit bottles and were visually distinguishable from the replica seal. Lab testing confirmed that both the replica seal and the adhesive used to affix it did not match the original, authentic foil and adhesive used on authentic Gilead product.”

Besides the physical evidence of the packaging—and analysis of the pills therein—the Gilead case is built on shoddy tracking of the bottles’ serial codes. Those codes, put in place under the 2013 Drug Supply Chain Security Act (DSCSA), and carried through the tracking history of transactions, showed that falsified codes or documentation was part of the scam. During the course of the investigation, Gilead challenged various actors in the counterfeiting ring to document their transactions, but responses were either not forthcoming, or were faked. This is one of the more prominent instances in the US where DSCSA compliance was a factor in a counterfeiting investigation.

In its August notice, Gilead stated that it “continues to work closely with the FDA, pharmacies, and legal authorities” to prohibit the distribution of the fakes; meanwhile, the 

 article notes that Gilead “has taken an under-the-radar approach, by hiring its own private investigators” while seizing the fake products. This raises a number of questions: there are penalties for violating DSCSA rules (although most of them are on hold until 2023) as well as various mail- and other fraud violations to pursue; further, there is an Office of Criminal Investigation in FDA (FDA-OCI) that brings gun-toting law enforcement and handcuffs to effect arrests of counterfeiters. Where was FDA enforcement during this period, when patients were being dosed with dangerous counterfeits? FDA-OCI’s webpage

 lists a steady stream of arrests and convictions on various medical frauds, but none relating to the Gilead case.

In its civil suit, Gilead is seeking upwards of $25 million in penalties from each of the accused actors; resolution of this will be in the future.

- Nicholas Basta is Editor Emeritus and Founder, Pharmaceutical Commerce

https://www.wsj.com/articles/drugmaker-gilead-alleges-counterfeiting-ring-sold-its-hiv-drugs-11642526471

https://www.gilead.com/news-and-press/company-statements/gilead-warns-of-counterfeit-hiv-medication-being-distributed-in-the-united-states

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/criminal-investigations/press-releases

In a civil action, Gilead alleges an extensive, transnational counterfeiting ring of HIV and other drugs

Gilead’s case against an alleged $250-million counterfeiting ring—what happens next?

It could be that years from now, when the dust has settled, there will be books and Harvard Business School case studies on the successful implementation of the US Drug Supply Chain Security Act (DSCSA), written into law in 2013. But for now, the outlook is still murky, as there are still substantive obstacles between the law’s interpretation by FDA, and the capability (and willingness) of industry to comply. Complicating the matter, the pharmaceutical supply chain participants who have made the biggest investments in DSCSA compliance (manufacturers and wholesalers) have less to do with the nominal purpose of DSCSA—to prevent counterfeit or substandard drugs from reaching patients—than hospitals and pharmacies, yet those supply chain partners are less ready to meet the 2023 deadline for regulatory compliance.

One result of this situation—not readily admitted to by most parties close to the evolving regulatory picture—is to delay implementation beyond 2023. It can be argued that FDA has acclimated industry to such delays by at least a year, as it did in past years when intermediate DSCSA deadlines were postponed. Most recently, it pushed the final few regulatory deadlines from late 2019 to 2023, essentially saying that everyone should get to the finish line then. For its part, the Healthcare Distribution Alliance (HDA), in a recent statement, cautioned “industry should not make this assumption [of a postponement]. In fact, in FDA’s recent public meeting, they once again stated that they expect industry to meet the end goal on time.”

All of which is not to say that FDA and industry are standing pat until 2023. Both have been busy, the former with issuing some (overdue) guidances for industry compliance, and the latter with beavering away at a variety of technical issues that will make DSCSA compliance ultimately successful.

In its latest (November) annual “Readiness Survey,” HDA found that 40% of manufacturers were set to send DSCSA-compliant data to their wholesaler trading partners; conversely, 60% of HDA members were ready to accept such data (both of these are 2023 requirements; both require weeks to months of coordination between trading partners to set up). The clock is ticking.

Last summer, FDA issued four guidances relevant to DSCSA, two of which finalized the agency’s stance, while the others were draft documents open for review. Of the latter, the “Enhanced Drug Distribution Security at the Package Level” document elicited an almost visceral response from HDA, which called for its complete withdrawal. “EDDS,” as people in the field call it, is meant to be the fruition of the 10-year slog to full DSCSA compliance. It would feature an interoperable, all-electronic system for trading partners to exchange serialization and product data throughout the regulated supply chain.

In presentations since issuing the draft EDDS guidance, FDA has made reference to an otherwise unspecified “system” by which it (or other regulatory bodies, such as state boards of pharmacy) would obtain tracking data on product transactions, with the nominal goal of verifying product authenticity and/or preventing counterfeit product from reaching patients. HDA’s objection:

“[T]he Draft Guidance seems to assume that all government authorities and trading partners are networked or connected in some unspecified way, that all transaction data held in the supply chain can be queried in a single request, that the system can return an automated response to that request, and that this enhanced system enables system-to-system, bidirectional connections and communications.”

“FDA’s vision is inconsistent with the law and vastly different from what the industry is building. If the agency were to move forward with a ‘system-to-system’ interface (in which trading partners would have access to other partners’ proprietary transaction data) or a proposed ‘communications hub,’ stakeholders will not be able to meet the 2023 deadline.”

Figure 1. What HDA and the pharma industry does not want from FDA is a “communication hub” where all transaction data would come together for regulators’ review. Credit: FDA

Other organizations, including the Pharmaceutical Research and Manufacturers of America (PhRMA), the National Community Pharmacists Association (NCPA) and the Partnership for DSCSA Governance (PDG) voiced similar concerns. On the flip side, the National Association of Boards of Pharmacy (NABP) offered that its existing NABP e-Profile Connect, a “central services hub” that includes data “for over a million licensees ranging from individual practitioners and pharmacies to wholesale drug distributors and other regulated facilities” could be built out to facilitate gathering trading-partner data.

HDA’s and others’ objections to the EDDS guidance might boil down to an issue of “semantics,” according to one informed source; even if a fully automated system were technically feasible, there are many places in the process where some manual intervention is needed. Various commentators noted that FDA’s own language in the guidance is inconsistent—it speaks of an enhanced system in a “post-2023” environment, which could be any time after 2023 and not necessarily at that moment.

Industry groups, including PDG, HDA and others, are settled, more or less, on an alternative approach: a fully distributed data system (i.e., most if not all trading partners maintain their own databases of the transactions of products they control, with agreed-on linkages to poll each other), and a “one-up, one-down” method of tracing products. In practice, a regulator like FDA would come to a trading partner (say, a retail pharmacy) and query it as to the origin of products in its control. Next, the regulator would go to that previous trading partner and repeat the process.

Integral to the interoperability that these organizations hope for with their vision for DSCSA compliance is use of the EPCIS 1.2 communications standard, a protocol that has been developed by the GS1 US Healthcare organization. GS1, best known as the “owners” of global barcoding standards, has helped in moving industry along an interoperability path (including the 2D barcodes now in place on pharmaceutical packages in most of the world). Along with criticisms of FDA’s “community hub” concept, HDA and others have been beseeching FDA to simply standardize on EPCIS 1.2 for digital DSCSA communications. Whether or not FDA does so (the original legislation only asked for a communication standard broadly used internationally), EPCIS 1.2 might become the 

 standard simply by enough US trading partners insisting on it (a business not using such a standard would have a complicated issue to communicate with other trading partners).

Something that is not specifically laid out in DSCSA legislation—but will be essential for successful functioning in the post-2023 environment—is establishing a so-called “trust framework” whereby supply chain participants can trust the online identity of message senders and receivers. A fundamental concept in DSCSA is the “authorized trading partner” (ATP), which is usually set up between one seller and one buyer. But many aspects of DSCSA will require second- or third-hand transactions (the buyer’s seller, or the customer’s customer, for example) Without trust, a nefarious actor (pretending to be, say, a local pharmacy) could query an ATP supply chain participant for trading data to obtain drug data in order to then counterfeit that drug. As Bob Celeste, a longtime leader in DSCSA-related standards-setting, notes, “There’s the old joke of two dogs talking to each other, with one saying to the other, ‘Online, no one knows you’re a dog.’”

Celeste’s organization, the Center for Supply Chain Studies, is acting as a facilitator for both a working group at PDG, and a new effort, the Open Credentialing Initiative (oc-i.org). OCI brings together several manufacturers (Novartis, Genentech, Amgen and Sanofi), some DSCSA software vendors (TraceLink, rfXcel, RXscan, and other software vendors active in digital-identity technologies (LedgerDomain, Spherity); more participants are actively being sought. OC-I started up in September; it is aiming to establish “global and open standards [that] ensure no vendor lock-in.” The PDG working group has similar goals. In recent months, both Spherity and LedgerDomain have run pilots that demonstrated the usefulness of being able to verify trading-partner identities quickly and reliably.

Should this credentialing initiative go forward, there are at least two looming problems ahead. One, industry will have to coalesce around some third party who will be the repository of the identities, and the grantor of credentials. At the same time, another component of DSCSA, a federal requirement to register drug wholesalers in the US, is yet to be finalized by FDA; it’s possible to conceive of a situation where the private sector will be better equipped than FDA to register legitimate wholesalers—but, the law is the law.

Another enabling technology of DSCSA compliance, but one—like credentialing—not specially called out in the legislation is managing drug master data. Master data, in a simplistic sense, is the information about a manufacturer’s products, not including (unless required) current transaction data. Access to this information helps DSCSA trading partners keep track of which products are in circulation.

At its Traceability Seminar in mid-November, HDA included a demonstration of the Global Data Synchronized Network (GDSN), a years-old effort by GS1 to provide a digital network for storing and communicating product data. The presenters, which included representatives of Walmart Pharmacy and AmerisourceBergen, have been working on basic business rules to set up such a network. In practice, GDSN calls for a group of participants in a supply chain to subscribe to a “data pool” where product data is uploaded, updated and downloaded by the pool subscribers; one advantage is that the product data need only be updated once and then is available to all pool participants (as opposed to a company needing to send new information to each of its customers).

Here, it’s worthwhile to pause to consider the difference between such a data pool and the FDA “community hub” that HDA has been so exercised about. While both systems nominally connect everyone together, the master data pool is only for product descriptions, and not ongoing trade or transaction information. According to an HDA spokesperson, “GDSN is a way to share item master data consistently through the supply chain. That is a key hurdle now and is often why files ‘fail’—due to incorrect master data. It’s fundamental to receiving product and sending EPCIS files, as master data must be received and contained within the system prior to receipt of the product (either at distribution or at the dispenser level). GDSN does not exchange transaction information; that will still be done via EPCIS.”

Outside of pharma, GDSN has been very successful—tens of millions of products, across multiple industries, have been organized into data pools. Much of the US medical device industry has already adopted GDSN. There are other approaches to an industry-wide pool for product data, and DSCSA vendors like TraceLink and SAP have master-data offerings in their suite of services.

The 2013 DSCSA law envisioned a 10-year process to bring the national, electronic, interoperable system to fruition; it’s now in a two-year “countdown” to completion. At this point, industry and FDA might make it to the finish line in a timely manner and it might not; for now, the key is that industry continues to make progress.

Building a data-sharing system for the US Drug Supply Chain Security Act (DSCSA) is two years from a mandated completion—will industry be ready?

Ups and downs in the march to DSCSA compliance

Handing off drug samples to healthcare professionals (HCPs) is a time-honored, integral part of pharma sales and marketing; the industry commits the equivalent of tens of billions of dollars to it in the US and abroad. For sales reps specifically, it is often the best or easiest way to get into the HCP’s office. Nor should it be ignored that since the late 1980s, the activity has been highly regulated by the Pharmaceutical Drug Marketing Act (PDMA), which created the need to document how samples are distributed.

Potentially, the sampling practice would have been upended by the pandemic (no, or drastically reduced, sales calls) except for two factors: FDA relaxed some PDMA requirements in early 2020; and the service providers to pharma for sample accountability—a relatively small number of specialized firms—had already developed digital tools to enable samples to be delivered at HCP request.

FDA’s action came very early as the pandemic settled in—its June 2020 

 (still in effect as of this writing) altered the request and signature requirements of PDMA:

FDA does not intend to take action against a manufacturer or authorized distributor of record that accepts alternate ways of verifying delivery and receipt of drug samples instead of obtaining the signature of the person acknowledging delivery…

Additionally, the guidance explicitly allowed for samples to be delivered to the HCP’s home, or an associated hospital or pharmacy (there was no specific guidance on this previously). Somewhat controversially, the guidance also allows for delivery to the home of a patient under that HCP’s care.

The main rationale for these modifications was the dramatic drop-off in patient visits to doctors’ offices, as well as the equally dramatic increase in telemedicine. Telemedicine went from 4% of patient-HCP interactions to 60% “practically overnight,” says Maria Whitman, global head of pharma and biotech at ZS, the professional services firm. “The importance of sampling became evident,” she says, “and patients and doctors were looking to manufacturers to find workarounds” to the lack of in-person sample delivery.

As a result, manufacturers dusted off, upgraded or swiftly adopted various e-sampling technologies that have existed in the industry for years, but were only slowly being adopted. “The e-sampling and direct to practitioner channels—which used to be an option—have now become table stakes for the vast majority of customers we support,” declares Eric Johnson, chief commercial officer at J. Knipper, one of the industry leaders in sampling management services. Data the company collected on its digital platforms show a more-than 2x increase in digital sampling channels starting in April 2020 (see chart below). That gradually declined over the next seven months, as sales reps returned to the field, but still well above the March 2020 level.

“For years, I’ve been talking about the value of a multichannel approach to HCP interactions by pharma,” adds Mark Jara, CEO of RxS LLC, a New Jersey firm exclusively dedicated to sample management and related services. “When Covid-19 hit, pharma sales organizations weren’t prepared for the all-virtual environment, but our digital platforms were embraced quickly, and it has just increased exponentially since.”

Industry data cited by Jara and others describe a situation where around 70% of sales rep-HCP interactions were face-to-face pre-Covid, which temporarily went to zero during the early lockdowns. It has since revived to around 30% of interactions—the rest being various virtual calls or digital communications.

E-sampling has taken on a variety of forms, tailored either to the desires of HCPs requesting the samples, and/or the compliance needs of the manufacturers, as well as their preferred marketing methods. A basic form allows a rep (or the CRM system the manufacturer is using) to send a sample-request form to the HCP; this can be accompanied by the digital signature of the HCP, along with required address and affiliation information. Another version allows the HCPs themselves to initiate the request.

J. Knipper announced an upgraded platform, SamplicitySA, in August. The platform enables direct-to-practitioner, direct-to-rep and direct-to-patient ordering; the direct-to-practitioner version is initiated by the HCPs themselves. The “SA” component of SamplicitySA is enhanced sample accountability through a user dashboard. Other components of the platform enable analytics and connection to Knipper’s in-house sales support services (Knipper handles both the software development of Samplicity, as well as order fulfillment and sales support).

At RxS, there are three interrelated systems: LinkedRx, for overall sample management, accountability and reporting; TeleTargetRx, for accompanying telemedicine/virtual sales situations; and SampleCentral, a portal for HCP-initiated sample requests. The latter emphasizes an “HCP-centric” approach, says Jara; some physicians (especially those in “no-see” offices that don’t permit rep visits) prefer to manage their own sample activities. The system is device-independent, running on smartphones, tablets or desktops. “It’s a customer-centric process, but the rep is still involved,” he notes. “He or she can note what the doctor is ordering, and interrupt the process to, for example, arrange a conversation with that person.” Overall, the platforms are intended to give reps a fuller “toolkit” for managing HCP interactions.

SymmetryRx provides a self-service (for physicians) sampling portal, complete with e-signature and e-request features, as well as an IT system, branded as RadiusXP, that can be used by pharma sales teams directly. Most recently, the company built out a direct-to-patient sampling platform.

Data-services firm IQVIA for the global pharma industry, provides a suite of IT solutions for sample management, regulatory compliance and allocation optimization, and works with a strategic partner to provide field services (such as auditing inventories at field offices). These services can interact with the overall CRM solution of the firm, Orchestrated Customer Experience (OCE).

For their part, both RxS and J. Knipper are strategic partners of Veeva, the leading CRM platform for life sciences sales teams. RxS’ Jara says his company’s software can pull data out of, or provide input to, a Veeva implementation to meet pharma needs.

Other pharma CRM systems, such as StayInFront, Synergistix or Salesforce.com, have various levels of data-sharing or actual sample-accountability management; Synergistix, for example, offers in-house support for regulatory compliance and reporting.

ZS’ Whitman says that the pharma industry struggled mightily to react to the pandemic shutdowns in switching to vendor solutions like those listed above, or to modify their own internal processes. “There were some bumps along the way, early on, with some physician practices complaining of a lack of sample availability, and some worried about an oversupply,” she says. “It took some time to get the right business rules in place.”

Based on surveys ZS has conducted, roughly two-thirds of primary care physicians, for example, complained of a lowered availability of samples; on the other hand, 73% of oncologists and rheumatologists said their needs were being met.

There could be a particular reason for samples’ emphasis in oncology or related specialties, many of which involve injected biologics: a sample prefilled syringe gives the physician an opportunity to guide the patient on proper self-administration of the drug. “Avoiding a second visit to the doctor’s office to get a demonstration is a value-add for both the patient and the physician,” says Whitman. “Before Covid, and after, pharma marketers in these specialties are concerned with losing patients between diagnosis and treatment. Providing this service is in the mix of patient services and support.”

Mention of biologics and oncology also highlights another aspect of sample accountability: ensuring that the right physician specialties are getting the appropriate samples. “Under PDMA, there are inclusions and exclusions for samples based on the medical specialty,” notes RxS’ Jara. Physician affiliations and practice areas need to be documented to justify distributing samples to that physician. According to Jara, this is another reason to consolidate sample administration on one platform across sales teams and across medical specialties—otherwise, the left hand might not know what the right hand is doing.

One aspect of sample distribution during the pandemic whose future is still undetermined is direct-to-patient servicing. “So far, we’re seeing this as having limited appeal; industry is waiting for clearer direction from FDA,” says Jara. There are numerous risks to the manufacturer in this practice, even with the intercession of the physician making the request.

Johnson of J. Knipper describes the elaborate process on the sample-fulfillment side for direct-to-patient. “First off, the physician’s request for a sample is treated as protected health data, and from this point on, the data will be housed in a separate set of data tables with no visibility to our clients and a small subset of need-to-know people on the Knipper side.” Then, the system checks to see if both the physician and the patient are in a state that allows direct to patient sampling. The order is then processed against standard compliance business rules as well as client business rules. Finally, if the order passes all of those business rules, it is transferred to the warehouse to be fulfilled.

Still, as Whitman points out, it is likely that telemedicine will remain a larger component of office practices after the pandemic and, if so, direct-to-patient sampling might be equally popular. ZS’ physician-survey data show that providing samples is one of the highest-cited benefits the pharma industry can provide, second only to financial support for patients.

A dramatic shift to e-sampling has been the effective counter to the reduced number of rep visits to physicians’ offices