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As our publisher Mike Hennessy Jr. discusses in his "Publisher's Note," I have noticed along my travels that efforts to comply with the 2013 Drug Supply Chain Security Act (DSCSA) has been a top priority among the links that make up the aforementioned supply chain. Perhaps it was great timing that I had the opportunity to attend the Healthcare Distribution Alliance (HDA)’s annual Distribution Management Conference, which was held in Indianapolis in March. This event was special to me, given that it was the first time I’ve covered one of the association’s conferences in person, as opposed to virtually. HDA also considers this one to be its largest supply chain education event.

Although I began to reference this in my show coverage last month, I think it’s worth reminding folks that there were a wide range of topics presented at the conference for attendees to take advantage of—ranging from DSCSA coverage; traceability and serialization standards; environmental, social, and governance (ESG); and a 340B update. The topic of 340B—which was last in my list for no specific reason—featured a session held by Andrew L. Wilson, PharmD, FASHP, McKesson’s VP of 340B solutions. Wilson described how the program’s inception dates back to the early 1990s, when the Veterans Health Care Act of 1992 (VHCA) enacted Section 340B of the Public Health Services Act. In a nutshell, it allows “covered entities” to purchase “covered outpatient drugs” at reduced pricing for dispensing to “eligible patients.”

So what makes a place of business a “covered entity?” One must apply for participation, while also meeting entity-specific requirements that are set out in the statute and interpretive regulations, some of which include, but are not limited to:

Being a government-owned or controlled hospital.

If non-government, a non-profit that has an agreement with a government entity.

Must be listed on the Health Resources and Services Administration (HRSA) 

Covered entities must also determine whether they will be using 340B drugs for their Medicaid patients (known as “carve-in”), or if they will be purchasing drugs for their Medicaid patients via other mechanisms (known as a “carve-out”). This is to avoid what Wilson calls a “double-dip,” formally known by HRSA as duplicate discount prohibition.

I would be remiss not to mention that the 

 team also attended Informa’s Patient Assistance & Access Programs (PAP) show last month in Philadelphia. We took advantage of the opportunity to attend a plethora of educational seminars at our disposal—with topics ranging from “improving the patient/HCP experience while reducing overall operating costs,” to “taking a digital approach to solving the fragmented support service experience."

 with SMEs in the space. We look forward to sharing this content with you all very soon.

Nicholas Saraceno is Pharmaceutical Commerce's Editor. He can be reached at

DSCSA, 340B among the headliners at the Healthcare Distribution Alliance's Distribution Management Conference.

Keeping Up with the Action

Over the last few months, biopharmaceutical firms have been more vocal than ever about challenges in the European business environment. The likes of 

 have openly or more discretely focused attention away from Europe in favor of the US and China. Ironically, this is happening at a time when the US is implementing a first step toward price controls through the Inflation Reduction Act (IRA).

What makes the European changes even more alarming than the disruptive changes in the US? As you probably know, the European single-market government payers have been able to extract prices for drugs that can be significantly lower than in free-market systems such as the US. Whether you believe that US prices are too high or not, the fact is they are in general higher, suggesting that patients who live in a free-market system for prescription drugs are subsidizing governments and patients in single-payer monopsonies.

European governments are struggling to make ends meet due to the economic recession following COVID-19, along with the impact of the war in the Ukraine. Let’s look at some of the specific changes.

 Sometimes coined as “AMNOG 2.0,” the German government has significantly tightened the evidence requirements for orphan drugs, essentially requiring a major or considerable benefit demonstration for commercial viability. In addition, it introduced discounts for combination drugs, shortening of the free pricing period from one year to six months, and an increase of the mandated rebate to 19% for all drugs.

 has systematically extracted rebates for prescription drugs, so that the net drug budget has declined by 4.5% per year since 2011.

 Due to overspending of the National Health Service (NHS) on drugs, the government wants to 

 as a rebate, per the voluntary scheme for branded medicines pricing and access. This comes on top of a decline in willingness to pay by lack of consumer price index adjustment of cost-effectiveness thresholds since 1999. 

The Association of the British Pharmaceutical Industry

 notes that the share of healthcare budget spent on pharmaceuticals is only 9% in the UK, versus 15% in France and 17% in Germany.

 Has introduced a more formal cost-effectiveness criteria as part of national price approval. In an initial assessment, this can have a large impact on the number of drugs that will be viable for launch.

The European Commission is contemplating 

 that will reduce effective patent lives from 10 to eight years and/or make it mandatory for manufacturers to commercially launch their approved drugs in all EU member states, irrespective of the locally determined price. This is really concerning, since a mandatory launch at the lower range of European prices will quickly cascade throughout the region.

What does this all mean for biopharma? Should companies de-emphasize Europe as some have done? That depends. For products with strong evidence of patient benefit, there may still be a strong case to launch in Europe. In cases where the benefit is minimal, or where the company has not been willing to develop the required evidence, commercialization will be even less successful than it already was prior to these changes.

Interestingly, US IRA-related changes may make the hurdle to be prepared for European access needs less high. Instituting a timeclock to the Centers for Medicare and Medicaid Services (CMS) negotiations for every new drug may motivate companies to develop stronger evidence and prioritize larger indications before formal launch, as it will result in more rapid uptake and higher cumulative revenue until CMS price control kicks in.

Every situation is different; however, this is another indication that the biopharma industry needs to engage in more detailed global trade-off analyses that are well informed by a strong understanding of how evidence scenarios result in access and product utilization in the largest global markets. Many companies may still have some 

 to do in order to achieve this and go beyond lip service in delivering value.

Ed Schoonveld is a value and access consultant, and author of The Price of Global Health.

How various factors are affecting the amount of funds allocated to healthcare.

Assessing Drug Pricing in Europe

The development of medications that are safe and effective for children has always faced stiff headwinds, in terms of not only the need to demonstrate drug safety and efficacy in children of varying ages, but the need to establish appropriate, evidence-based dosing and identify potentially life-threatening drug-drug interactions. The reality is that children are not just small adults, as they experience drastic physiological changes throughout childhood—from infants to toddlers, to young children to teenagers. In addition to the mandate of establishing safety and efficacy and developing dosing guidelines, other challenges arise with the need to select the most acceptable dosage forms that are both tolerable to pediatric patients and still able to meet drug bioavailability requirements, while reducing the potential for adverse events and toxicity.

Meanwhile, ethical and operational challenges arise during the clinical trial stage. “Pediatric trials are notoriously difficult to recruit for, as parents are understandably reluctant to enroll their children into intrusive or invasive studies, and there may be a possibility that the child will be randomized into a placebo treatment arm,” says Karen Rowland Yeo, PhD, senior vice president, client and regulatory strategy for the Simcyp division of Certara.

Similarly, the financial opportunities associated with developing pediatric medications are often limited, in part, by relatively small market sizes and the need to investigate, formulate, and commercialize parallel versions of any given drug. For example, when commercializing a therapy for children of different ages, investigators may need to evaluate liquid vs. solid form, tablets vs. capsules, injectable or intravenous options, the use of smaller soft gels, chewables or orally disintegrating tablets, and more, and commercialize several different forms of the same product for different age groups.

Collectively, these considerations create barriers for drug developers, and frustrating gaps for pediatric patients and their families. And too often, this puts a burden on physicians and pharmacists, who have no choice but to prescribe therapies that are approved for adults off-label and use their best judgment to arrive at an appropriate dosing strategy for their pediatric patients.

While various regulatory and financial incentives (discussed ahead) have helped to spur interest and innovation in the pursuit of medications that are explicitly studied in and approved for use in children, today, roughly 60% of treatment that are prescribed for children are not approved for pediatric use (rather, they are prescribed off-label), and the percentage of FDA-approved medications is even smaller for neonates, with 90% of drugs used in this patient subgroup being prescribed off-label.

Yeo points to off-label prescribing as an integral part of contemporary medicine. She notes that children benefit from drugs that are not approved for use in the label by FDA or other regulatory health authorities, and in many cases, an off-label medicine may provide the best available intervention for a patient, as well as the standard of care for a particular disease. Nonetheless, Yeo adds that the off-label use of any therapy—and reliance on trial-and-error dosing strategies—is particularly challenging when it comes to children, as drug solubility and absorption is impacted by smaller gastric fluid volumes compared to adults, and organ maturation in young patients changes rapidly over time.

Although the majority of off-label clinical decisions are based on the principles of evidence-based medicine, and regional working groups typically put recommendations in place for drugs used off-label, high-quality data are rarely available to support dose extrapolations in children.

“It is not always obvious how important factors change when going from adults to children,” explains Yeo. “Growth, maturation, and environmental factors, along with disease and genetic factors, can affect drug performance in children, especially in those less than two years old.”

Thus, it is never as simple as just scaling down the adult dosage on a linear basis.

“There is no magic formula to convert adult dosages for children, and choosing a dose that is simply being proportional to weight or volume may not be appropriate,” says Christian Frois, partner at Trinity Life Sciences, a provider of global life sciences commercialization solutions. “Too much medicine increases the risk of adverse events, while too little may lead to a lack of clinical efficacy for the patient.”

“This lack of approved labeling and dosing recommendations could also lead to a higher risk of medication dosing errors, adverse events, side effects, drug-drug interactions, or allergic reactions in pediatric patients,” adds Shipra Patel, MD, global therapeutic area section head, endocrinology, and global head, pediatrics for Parexel.

Adding to the complexity of broad off-label use of any medicine is that patients often face bigger affordability challenges, as most payers don’t automatically cover off-label use of approved therapies, notes Jan Nielsen, patient solutions division president for AssistRx. “To help patients overcome this barrier, we help the physician’s office to write letters of medical necessity and apply for compassionate use to encourage payers to cover the drug," she says. "If that fails, we turn to other community resources to help patients and their families address the affordability gap.”

There is, however, one important silver lining to the broad use of off-label prescribing in pediatric medicine.

“Today, there is growing physician [and regulatory] enthusiasm and need for real-world evidence (RWE) and investigator studies to support drug development and the use of the therapy in pediatric populations,” notes Frois.

Specifically, clinical studies that are conducted to obtain real-world data (RWD) and create RWE for therapies that are frequently prescribed off-label for pediatric patients are being used to provide data-driven dosing recommendations for specific pediatric age groups.

“There is a greater appetite for embracing innovative study designs, when applicable, to help reduce patient burden,” says Patel. “These novel approaches include the use of adaptive trial designs, decentralized approaches, and increased development and use of RWE.”

Government agencies are keenly aware of the need for more and better pediatric medicines, Yeo points out, and have been attempting to address these gaps through regulatory mandates. In the US, two pivotal regulatory frameworks have been in place for over a decade to encourage and incentivize drug sponsors to develop new pediatric medicines and to pursue pediatric indications for existing medications.

The Best Pharmaceuticals for Children Act (BPCA):

 A voluntary program that incentivizes pharmaceutical companies that voluntarily perform pediatric studies by 

providing the opportunity to gain six months of pediatric market exclusivity.

The Pediatric Research Equity Act (PREA): 

A mandatory program that authorizes FDA to require pediatric assessments for certain drugs and biologic products (either at the time of initial drug submission or later), unless the assessment has been deferred or waived.

In August 2020, the Research to Accelerate Cures and Equity (RACE) for Children Act—an amendment to PREA—went into effect. With the RACE for Children Act, FDA is now authorized to require drug sponsors to submit an initial pediatric study plan (PSP) with any original new drug application (NDA) or biologics license application (BLA) oncology product that may target the growth or progression of a pediatric cancer. And, importantly, new cancer therapies with orphan-drug designated indications will no longer be exempt from PREA.

In addition to requiring pediatric drug development, “regulators are also providing guidance as to how the development process may be streamlined,” says Yeo. “Both FDA and [the European Medicines Agency] indicate that pediatric clinical trials should be designed to fill knowledge gaps, and the agencies encourage the use of innovative approaches, including modeling and simulation.”

Since going into effect in 2012, BPCA and PREA have resulted in more than 900 products with specific pediatric use information in their label.

 And in FDA’s latest annual status summary,

 the total number of medications involved in pediatric studies numbered 394 in 2019, 398 in 2020, and 400 in 2021, reflecting steady progress since FDA began compiling such data in 2007. (During that first year, pediatric studies were conducted for 190 products.)

Managing any chronic or life-threatening condition is always a challenge, but it is particularly difficult within the realm of pediatric care.

“When families are taking care of a child who is sick, managing the disease and complex medication regimens, and other medical interventions, along with logistical and financial demands, can be overwhelming and scary for parents,” says Nielsen of AssistRx. “Providing thoughtful, comprehensive support is critical to ensure success for both the patient and the drug manufacturer."

Such support, Nielsen continues, could include helping parents investigate all available treatment options to ensure drug affordability; providing nursing support to help parents master drug injection, complex medication protocols, and side effects at home; coordinating transportation; and supporting communication and access via channels such as text messaging.

Further, many specialty drugs have very complex titration requirements. “Our pharmacists support some specialty pediatric products by repackaging and color coding the prescription and clarifying for the child’s family when the medications must be taken with or without food for optimal efficacy,” adds Nielsen. “These specialists will also connect with the physician to alert if the patient is not tolerating the medication, when it’s time to move on to the next titration, and so on.”

When designing a constellation of wraparound services, it is particularly important to embed the elements right into the workflow of the physician’s electronic health record (EHR) systems to break down silos of information and streamline the offerings.

“You can have a great drug, but life gets in the way and emotion gets in the way, particularly when it comes to supporting pediatric patients,” says Nielsen. "The right mix of high-touch and high-tech elements to deliver the right wraparound services—in addition to the drug itself—can help to overcome the types of burdens that undermine affordability and adherence objectives.”

 methods to predict drug behavior in children

A key challenge in the design and execution of pediatric clinical trials is patient identification and recruitment. Sample sizes are typically small, particularly for studies in children that target rare disease. Also, there are often logistical challenges affecting the motivation of patients and families to participate in clinical trials, resulting in low patient enrollment levels in many cases. “For pediatric clinical trials, the needs of the whole family unit should be considered, not just the needs of the participant,” says Patel of Parexel. As alluded to, such needs could include support to families in the form of transportation assistance, meal vouchers, and other forms of wraparound support.

Patel cites other important factors for trial designers to be on top of in the pediatric space. Those include limiting blood draws for young children or prioritizing certain blood draws over others, and streamlining study designs to include only the most relevant endpoints and procedures that are needed to generate interpretable safety and efficacy data. Reducing the frequency of study visits and/or including some virtual or home visits could also lower overall study burden.

Significant physiological changes occur in children from birth to adolescence, leading to differences in pharmacokinetics (PK; which relates to the absorption, distribution, metabolism, and excretion of drugs in the body) and pharmacodynamics (PD; which relates to a drug’s molecular, biochemical, and physiologic effects). The impact of age and maturation can be simulated using physiologically based pharmacokinetic (PBPK) modeling—in lieu of clinical studies.

Specifically, today’s PBPK models integrate the complex interplay of human physiological parameters with specific drug characteristics, thus providing a mechanistic approach to predict the PK drugs in different patient populations. This approach allows investigators to create virtual pediatric patients by selecting actual physical characteristics that mimic the developmental physiology of children at different ages. Pediatric PBPK models integrate additional information regarding organ development and the pathways involved in the drug disposition. This data can help reduce the sample size of actual patients needed to make meaningful inference from pediatric study data than would be required for more empirical analytical methodologies.

“This may alleviate some of the challenges associated with pediatric trial recruitment and can assure that every study participant receives the study medication and not a placebo,” says Yeo.

 notes that the use of pediatric PBPK modeling increased 33-fold between 2005 and 2020, with most of the effort focused on clinical and drug-development applications.

And the use of such modeling techniques is expected to grow, in part, due to FDA draft guidance published in September 2022,which states that “planning for DDI (drug-drug interaction) evaluations should be included as a section of the initial pediatric study plan under pediatric pharmacokinetic studies and should address the impact of DDIs on drug dosing in specific age groups.”

 The draft guidance also states that “quantitative approaches, such as PBPK analyses, should be explored to address pediatric DDIs during drug development when differences in DDI are expected.”

In the years to come, machine learning and artificial intelligence are also expected to play an increased role in efforts to optimize pediatric drug development and improve trial success.

 The areas such tools, and overall advances in data analytics, are expected to bolster include predicting future clinical complications, improving the analysis of medical images, identifying relevant endpoints and biomarkers in pediatrics, and predicting treatment and placebo responders.

1. Allen, H.C.; Garbe, M.C.; Lees, J.; et al. Off-label Medication Use in Children, More Common than We Think: A Systematic Review of Literature. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677268/

2. Tereza, H.; de Lima Costa, M.; Costa, T.X.; et al. Use of Off-label and Unlicensed Medicines in Neonatal Intensive Care. 

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204427

3. Overview of US Pediatric Regulations. Institute for AdvancedClinical Trials for Children, April 26, 2022, 

https://www.iactc.org/resources/overview-of-us-pediatric-regulations/

Pediatric Studies – Annual Status Survey

5. Johnson T.N.; Small, B.G.; Yeo, KR. Increasing Application of Pediatric Physiologically-based Pharmacokinetic Models Across Academic and Industry Organizations. 

CPT: Pharmacometrics & Systems Pharmacology.

https://ascpt.onlinelibrary.wiley.com/doi/10.1002/psp4.12764

General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/general-clinical-pharmacology-considerations-pediatric-studies-drugs-including-biological-products

7. Goulooze, S.C.; Zwep, L.B.; Vogt, J.E.; et al. Beyond the Randomized Clinical Trial: Innovative Data Science to Close the Pediatric Evidence Gap. 

https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.1744

Innovation and investment in advancing lifesaving therapies for pediatric patients to the commercial stage remains a daunting task, but rapid advances today in modeling and simulation are reducing the hurdles for drugmakers.

Pediatric Medicine: Challenges Abound

The old truism that the US pharmaceutical supply chain was essentially impervious to counterfeits and illicit diversions has crashed against the realities of the COVID-19 pandemic and its aftermath. No, the US is not awash in counterfeits; but there are “dark corners” of the supply chain, from manufacturers all the way through to the delivery vans bringing drugs to a local clinic or pharmacy, that are not as reliable as they once were. There is also an appetite, brought on by all the controversy over COVID vaccines and therapies, for individual consumers to go their own way in choosing medications—buying from unreliable online pharmacies, or accepting treatments outside FDA’s purview.

“With the disruptions brought on by the pandemic, the urgent needs for COVID-19 therapies and other medications around the world, the readiness of counterfeiters to step in, and now the Russia-Ukraine war, the pharma supply chain has become a Wild West,” says Greg Cathcart, CEO of Excellis Health Solutions, a Drug Supply Chain Security Act (DSCSA) and supply chain consulting firm (now a part of NNIT, a global information technology company). “These disruptions have given drug diverters plenty of room to operate in.”

All this is happening just as the crowning achievement of pharma supply chain managers and regulators—the 2013 DSCSA—reaches its 10-year culmination.

By Nov. 27 of this year, all participants in the US’ pharmaceutical supply chain—manufacturers, wholesaler/distributors, pharmacies, and even certain logistics providers—are supposed to have a comprehensive, interoperable electronic-data system that enables drug packages to be tracked by individual identities, from maker to dispenser.

Data from multiple sources show the heightened threats the global pharma supply chain is under. The Pharmaceutical Security Institute, in its annual summation, counted 5,987 counterfeit incident reports in 2021 (the latest year studied), up 38% from the year before; over 40% of these were in North America. The BSI Supply Chain Risk Insights Report, published in January, found higher levels of thefts of all types (facility, container, vehicle, etc.) but one, and also reported that pharmaceuticals were the second-highest product type (behind food) subject to vehicle hijackings. In the US, it’s worth noting that FDA’s Office of Criminal Investigations had a very active 2022, with new announcements of thefts, diversions, and financial improprieties occurring almost daily (although it should be recognized that a significant number of these involve controlled substances).

These sorts of worries have elevated supply chain risk management to the highest executive levels in pharma. “The escalation of supply chain and digital supply chain risk up the c-suite agenda means that today there has to be a proactive approach, from the outset to the procurement of supply services,” says Mark Brown, a global managing director at BSI, in its 2023 report. “You can’t just go for the lowest cost—you have to assess the situation and understand that sometimes the lowest cost may increase risk and potentially harm your organization.”

Having “situational awareness” in real time is the essential capability to control risk and manage theft or misdirected shipments, according to Barry Conlon, CEO of Overhaul. The company was an early developer of software systems that could unite, for example, temperature readings of a cold-chain pharma shipment with truck-mounted location devices, and assemble these data to enable a physical intervention to redirect a shipment or recharge refrigerant. The company recently acquired FreightWatch from Sensitech, the Carrier Corp. division that specializes in temperature monitoring hardware. Conlon says that the FreightWatch acquisition broadens Overhaul’s global reach. “In 2022, our interventions resulted in $250 million worth of recovered product, and it should be emphasized that every dollar in saved product represents $9 in avoided cost for product replacement, litigation, and the like,” he notes.

There has been a small explosion in recent years in IT systems that can aggregate supply chain data and present it to logistics managers or shippers—these include ParkourSC, Roambee, Controlant, and others. Conlon says that a distinction can be made between service providers based on software only (like Overhaul), offering to interface with any sensor or tracking device, and those that offer a combination of the two. However, a common problem in the industry is getting cooperation from the hardware vendors (which could in fact include container suppliers that mount their own hardware), freight forwarders, and IT providers.

Manufacturers have already invested billions to imprint 2D barcodes on packaging, meeting an earlier DSCSA mandate; now, many of them are investing in case packing automation to enable them to aggregate case data, and for wholesalers to infer the contents of cases without opening them. (Technically, this is not a DSCSA requirement, but wholesalers have been adamant that their highly automated processes would break down without aggregation/inference, and a couple years ago, FDA essentially blessed this process.)

Upsher-Smith Laboratories, a Morton Grove, Minn. manufacturer, recently opened a new “Plant C” that brings together new serialization capabilities. “We’re still pulling it all together,” says Adam Conlon, associate VP of operations, while noting that Upsher-Smith makes not only its own branded products, but also brings in product manufactured by contract manufacturing organizations (CMOs), and, with the new capacity, is planning to become a CMO for others. “We wouldn’t mind having more time for the DSCSA deadline, but we plan to be compliant by then.”

Tim Donelson, director of serialization and manufacturing IT at the company, notes that Upsher-Smith took a two-phase approach, selecting Optel Systems for barcoding technology earlier, and now has case-packing machinery on order for delivery later this year. Uhlmann bottling equipment is doing both serialization and aggregation on certain lines. Some packaging lines will have a semi-automated aggregation process, including 2D “helper” codes to manage bundles of product, adds Donelson.

Conlon says that the company, besides being able to serialize its own production, that of its CMOs, and eventually for clients for whom it is a CMO, hopes to gain value by better management of quality control, and linking to an IT system for electronic batch records. All these operational and compliance capabilities are grounded in the Advanced Track and Trace for Pharmaceuticals (ATTP) system from SAP.

Harm is certainly on display for Gilead Sciences, which has concluded multiple sets of litigation against multiple pharmacies and so-called “fly by night” distributors who were either involved in selling and reselling diverted or counterfeit HIV medications, as well as fraudulently taking advantage of a free-drug distribution program supported by Gilead. In February, a federal jury convicted the head of Minnesota Independent Cooperative of selling diverted or counterfeit Gilead HIV and hepatitis C medications worth over $150 million; in March, a default judgment was granted by a Florida federal judge against Baikal Marketing Group and others amounting to $175 million for the free-drug program abuse. Last year, another diversion/counterfeiting case, involving dozens of parties in 10 states, led to an injunction under the Lanham Act, which allows brand owners like Gilead to seize counterfeits prior to resolving legal actions.

“Gilead uses various measures to help ensure safe and secure supply of its products, including having authorized pharmaceutical distributors of record, as well as utilizing anti-counterfeiting technologies,” notes a company spokesperson. In some of the investigations, DSCSA-mandated product codes and transaction documentation were key evidence. In fact, the company is critical of the DSCSA rule specifying the “sunsetting” of the Transaction History record, one of three types of tracking reports defined by the law; it would prefer to maintain this record after its November expiration, to help it track its products’ distribution.

Long before DSCSA or any data-driven tracking process, the pharma industry has used a wide variety of anti-counterfeiting measures to protect its brands. Broadly speaking, these techniques—which are widely used in consumer goods and other markets—can be overt (recognizable by the end customer), covert (hidden but identifiable by inspectors), or forensic (verified by laboratory analysis, often with a view toward building a legal case).

Most of these techniques involve the packaging or containers of pharma products (some have been proposed for the products, such as pills, themselves). Thus, security printing or microprinting has been applied; holograms have been embossed onto packages, and taggants incorporated into packaging paper or ink.

One example is Schreiner MediPharm, which provides labeling technology for manufacturers of products in vials or syringes. In the past year, it has introduced Syringe-Closure-Wrap (for prefilled syringes) and a similar tamper-protection label for vials. In both cases, the labels clearly show if the container has been opened (in cases where counterfeiters might reuse the container); other security features can also be incorporated into the label.

A new offering might be in the works for Sicpa, a provider of security inks. Last year, it announced an expanded partnership with UbiQD, a Los Alamos, NM developer of quantum dot (QD) technology. QDs are nanomaterials that exhibit the effects of individual atoms—in this case, photoluminescence that can be “tuned” to various colors. That combination of properties creates possibilities for uniquely identifying commercial products in a near-impossible-to-replicate manner.

Nanomaterials are also the target of TruTag Technologies, which has been offering a microporous silica particle that can be encoded and then authenticated. The particles, qualified by FDA as “generally regarded as safe,” can be combined with excipients into drug formulations. The company has announced a partnership with Gerresheimer, the Dusseldorf manufacturer of glass packaging. In this case, however, Gerresheimer is seeking to incorporate the TruTags onto the glass packaging surface, initially for cosmetics products.

In January, TruTag also announced the formation of a Smart Medicines Advisory Board, to accelerate development in the pharma field.

“Smart” is a recurring theme with pharma labeling and packaging, with various vendors or collaborators seeking to combine product authentication with tracking, medication adherence, clinical-research data gathering, and other applications. The use of radio-frequency identification (RFID) labels is one element of these smart applications. Such efforts are promising but seem to be limited by the significant coordination needed between different internal groups at pharma companies. Moreover, “Going beyond the steady amount of packaging authentication activity in the industry today is limited by the multi-million-dollar contracts for DSCSA readiness,” says Excellis Health’s Cathcart.

Even though compliance with DSCSA is a mere seven months away, critical programs are still being finalized. In late 2022, the GS1 US Healthcare organization published Release 1.3 of 

“Applying GS1 System of Standards for DSCSA and Serialized Interoperable Traceability,” adding to the Release 1.2 document published in 2016. Tracy Nasarenko, director of community engagement at GS1 US Healthcare, explains that the 1.2 document should still be the starting point for new participants in DSCSA compliance; Release 1.3 includes refinements or enhancements on applying GS1 terminologies, and includes how to encode “22 serialized supply chain choreographies” in XML—the latter coming from workgroup discussions on how supply-chain events should be handled.

Looking at the concerns expressed by the 50 or so organizations participating in the GS1 workgroups, Nasarenko comments that learning the nuances of EPCIS standards, including the “common business vocabulary” (CBV) by which information is transmitted, will be an ongoing exercise for the pharma industry. “Communicating the right master data (i.e., the basic descriptions of what a product is and who made it) is causing issues,” she says. Use of the GS1-defined “GCP” (GS1 company prefix) is still a ‘work in progress.’”

Another group active in developing guidance to help the industry is the Partnership for DSCSA Governance (PDG), which brings together representation from manufacturers, wholesalers, dispensers, and solution vendors (FDA also sits in on the deliberations). In February, PDG released four chapters of a “Foundational Blueprint for DSCSA Interoperability,” addressing practical matters of transmitting information among trading partners.

“The expanded Blueprint is a critical milestone and will significantly contribute to the industry’s efforts to achieve DSCSA interoperability by the November deadline,” says Eric Marshall, PDG executive director. “While the Blueprint does not carry the force of law, it does represent the consensus best thinking of more than 60 of the nation’s leading DSCSA stakeholders.”

A third resource arises from the pharmacy community, specifically the National Association of Boards of Pharmacy (NABP). In March, the group announced that it will be launching the Pulse online service this summer to assist pharmacies (especially small ones that lack IT resources) in meeting their DSCSA responsibilities. The service, open to all pharmacies registered to their states’ pharmacy boards, will enable them to connect with their trading partners and to respond to tracing requests that might come in from regulators. Pulse “will provide access to user-friendly tools and a comprehensive network of verified relationships, enabling consistent communication with trusted trading partners of all sizes across the supply chain,” says Al Carter, NABP executive director.

The plight of small pharmacies has been an ongoing concern of DSCSA observers; warning signs have been flashing for years on this part of the pharma supply chain. In December, the American Pharmacists Association wrote to FDA, requesting an official finding from the agency that “enforcement discretion” (i.e., a delay in enforcement) would be allowed for pharmacies, in part because of FDA’s own tardiness in completing assessments and guidances.

However, the pharmacy community has not been standing still. Numerous hospitals and health networks have been installing software and systems for DSCSA compliance within their pharmacies. Most recently, Renown Health Foundation, a 150-site network in northern Nevada, has selected rfxcel’s DSCSA software. “This will enhance Renown’s ability to help protect patients from exposure to drugs that may be counterfeit, stolen, contaminated, or otherwise harmful,” says an rfxcel statement.

“Dispensers have entered the DSCSA discussion later in the game, and as a result, some of their unique needs were not well highlighted until recently,” says Herb Wong, rfxcel marketing manager. The company has also been participating in NABP-sponsored workshops for pharmacies this year.

One might have the impression that the private-sector solution providers—of which there are quite a few—is waiting for these consensus documents to be adopted before writing code that carries them out, but the reality is that many solutions are on the market. Vendors such as TraceLink, rfxcel, LSpedia, Systech, Axway, Covectra, and others voluntarily collaborated with the Healthcare Distribution Alliance a couple years ago to ensure that a verification router service (VRS) could be used to verify the authenticity of saleable returns at distributors.

Another industry-sponsored group, the Open Credentialing Initiative, is addressing the ongoing problem of verifying the identities of parties that might show up as authorized trading partners in DSCSA communications networks. Legitimate pharma supply-chain trading partners want to prevent the incursion of unauthorized or illegitimate parties, as well as to ensure that information requests are correctly routed.

One fairly new DSCSA-compliance vendor participating in the Open Credentialing Initiative is Trust.med. The company is developing a new approach to both trading-partner verification and to establishing EPCIS-compliant messaging, according to Dan Kraciun, CMO, VP operations. He explains that several years ago, Trust.med’s parent established ownership of the “.Med” top-level domain (TLD) with ICANN, the international body that standardizes the World Wide Web. When a DSCSA trading partner establishes an account with Trust.med, Trust.med can, in turn, establish webpage addresses (URLs) not just for that trading partner, but for each product it has. In effect, Trust.med uses the machinery of the internet to manage the security and the interoperability of DSCSA compliance.

Creighton says that Trust.med has lined up a handful of clients so far; he also emphasizes that Trust.med needn’t be looked at as an alternative to existing DSCSA software implementations, but as a complement that can extend them more efficiently.

One of the biggest worries currently in the industry is handling exceptions—cases where product identities cannot be read, or incorrect or incomplete information is transmitted during a transaction. The concern is that for minor or innocent reasons, a shipment might be held up or rejected until the data flaw can be corrected.

One solution vendor, LSPedia, is continuously updating a software module specifically for exceptions management, called Investigator. According to Riya Cao, CEO, AmerisourceBergen chose to implement this solution to avoid setting up a call center of nearly 100 personnel to anticipate manually handling exception queries. With Investigator, exceptions are automatically analyzed and predetermined responses, such as sending an email query to the appropriate trading partner, are generated. “These automatic processes can reduce the time to resolve exceptions from days to minutes,” says Cao. The company is currently about halfway through a multi-week pilot to gather more instances of exceptions and to broaden its applicability to more supply-chain participants. On top of that, LSPedia plans to add business-intelligence tools to Investigator so that a user could evaluate the quality of DSCSA data a manufacturer is providing.

“Eventually, higher-quality DSCSA data will become a competitive advantage,” adds Cao.

LSPedia also figures in an intriguing application of DSCSA capability—the so-called “value-beyond-compliance” goal that early promoters of DSCSA technology touted as the eventual payoff for the substantial investments the industry has made. In January, LSPedia announced a partnership with a company called Workd, whose software, MedMover, enables organizations to optimize matching-product sales with complementary products or services—the sort of capability Amazon provides to its users with its “recommendations” for follow-on purchases.

According to Cao, MedMover will analyze DSCSA’s item-specific data and suggest other products a wholesaler, for example, might recommend to its customers.

It’s hard to get too excited about such value-beyond- compliance applications when so much of the industry is struggling to get its basic DSCSA tasks in order. But those applications give a glimpse of a future pharma supply chain that is more secure, more responsive, and more cost-effective.

— Nicholas Basta is Editor Emeritus and Founder of Pharmaceutical Commerce.

As a November deadline looms for industry compliance with an interoperable system for product tracing, there is more urgency in the US pharma supply chain.

Ramping Up DSCSA Readiness Efforts

We live in a transformative time. Despite what many see as the end of the blockbuster drug era, the specialty drug market has never been more vibrant, with pharmaceutical manufacturers bringing in exceptional innovation with the most noble of intentions at its core: the desire to provide patients with medicines that target their specific needs around common and rare disease treatment.

Since early 2021, the FDA has approved 80 specialty drugs, with some experts predicting that a full two-thirds of the new drugs in 2023 will likewise be specialty therapies. The momentum is expected to continue . Nephron Research predicts the specialty pharmacy market could reach $375 billion by 2025, a 46% increase over projections for the current year.

Not surprisingly, getting these drugs to market involves myriad complexities, with each requiring stakeholders to effectively navigate a litany of often unique challenges. Patient hubs have emerged as the core technology infrastructure needed to guide and align all stakeholders—most notably manufacturers, healthcare providers, and patients, but also specialty pharmacies, insurance companies, and regulators—through the entire specialty or experimental drug journey.

Patient hubs have evolved rapidly, as the specialty drug market has grown and the demand for greater patient access, engagement, and drug performance tracking has increased. Several noteworthy developments reflect this shift and should be considered by manufacturers as they plan for patient hubs in the future.

Delivering an improved patient experience

Today, patients and providers enjoy a patient hub experience that guides them through every step of the specialty drug journey that starts with a customer-facing portal designed to deliver an intuitive and pleasing user experience. Featuring everything from advanced customer relationship management (CRM) software, virtual assistants and chatbots, and telehealth, patient hubs now welcome prospective patients, assess them against the therapy’s needs and provide them—along with their doctors—with the information, documentation, and guidance they need on everything from enrollment, to financial assistance, and even post-treatment care.

They also dramatically improve patients’ adherence to treatment regimens with autonomous appointment reminders and automated assistance. This helps patients ensure they follow each therapy's unique protocols, putting them a click away from assistance from an expert available via a call center or an ad hoc telehealth appointment that is facilitated through the hub.

It’s worth noting that today’s advanced hubs integrate directly with the patient’s electronic health record (EHR) while continually gathering data from wearables and other devices. Not only is this real-time data valuable to gather for analysis ultimately used to demonstrate drug efficacy for FDA approval, but perhaps most importantly, to monitor the patient’s progress and well-being. When applicable, claims and reimbursements with payers are also processed and managed with ease.

Robust reporting capabilities and interactive dashboards also make all data, including information consolidated in data lakes and other repositories, immediately accessible for use by clinical trial teams’ decision support—all while reducing administrative burdens and controlling escalating costs.

Historically, managing patient hubs was a significant IT burden for manufacturers, who had to create a hub for each drug brought to market, as well as those they wanted to, or were required to, continue gathering data on; for example, reporting for the FDA’s risk evaluation and mitigation strategy (REMS).

Because of this, many specialty pharmacies began offering their own patient hubs, providing manufacturers with a way to outsource their creation and management. In time, as patient hubs became more complex and grew to encompass a much wider array of business functions, data formats, and technologies, these have arguably become problematic as well. Today’s patient hubs are simply too sophisticated to create and manage at scale for organizations that are pharmaceutical developers and manufacturers at their core.

With its ability to provide computational power inconceivable just a few short years ago, the cloud makes it possible to create patient hubs with capabilities that historically were cost-prohibitive in on-premises systems. Highly distributed, cloud-based systems can also be developed and deployed faster than ever before, making it possible to effectively and quickly build patient hubs that are uniquely tailored to address the patient engagement needs associated with each therapy. For example, a clinical trial drug might require cold chain storage to ensure its efficacy. Using integrated sensors and advanced integration and messaging technology, today’s cloud-based patient hubs can be configured to enable patients, physicians, and the manufacturer to know in real-time if the temperature of a dose was compromised during its transportation or storage.

Offered in an operating expense (OpEx) model and with razor-thin margins for storage and compute without expenditures for hardware, cloud-based patient hubs are generally less expensive, empowering pharmaceutical companies to benefit from high-performance patient support programs that cost less to implement.

Incorporate new technologies and capabilities

Delivered as a service, patient hubs now bear little resemblance to their on-premises predecessors. The advanced, multi-faceted cloud infrastructure and services they make possible enable manufacturers to benefit from the modular, plug-and-play capabilities of cloud-native applications that can be quickly developed, deployed, and integrated seamlessly. Patient hubs can also consolidate, analyze, and act on data in multiple formats—including HL7, FHIR, and EDI—and from myriad sources, among them the EHR, pharmacy benefit managers (PBMs), specialty pharmacies, and health information exchanges.

Patient hubs can also integrate with operational systems and disparate business functions with relative ease. For example, enabling companies to track each patient’s specialty drug journey with its core customer relationship management system, while simultaneously empowering operational teams to use existing business intelligence systems to organize and visualize vast amounts of information for evidence-based decision-making.

Today’s patient hubs incorporate many technologies, from machine learning to advanced analytics, artificial intelligence, and blockchain. Creating and building them requires teams with extensive development, deployment, and data protection expertise.

Because of healthcare’s highly regulated nature and the need to move, access, analyze, and safeguard personal data, patient hubs also require teams with deep technology domain expertise. This includes not only experience with use cases like telemedicine and some of the data formats mentioned, but also familiarity with industry regulations, such as the Health Insurance Portability and Accountability Act (HIPAA) and certifications like the Health Information Trust Alliance (HITRUST).

Perhaps not surprisingly, this has given rise to companies that possess these technology and data-oriented skill sets. The cumulative impact of these developments is that pharma manufacturers are better positioned to increase the patient engagement associated with their specialty drug programs, their overall effectiveness, and ultimately, their ability to get new therapies approved and added to payer’s formularies.

Dhaval Shah, is EVP and head of the medtech business at CitiusTech; Simran Mittal, PhD, is assistant VP and consulting lead, also for the medtech business at CitiusTech.

With the rapid rise of the specialty drug market, manufacturers are increasingly relying on new advances used by patient hubs to boost their levels of patient engagement.

High-Tech Hubs and Specialty Pharma

The healthcare space is adopting and even requiring the digital processes that organizations have been driving the industry toward for over a decade. Regulators continue to emphasize innovation in healthcare, especially digital requirements for e-prescriptions, e-prior authorizations (e-PAs), and other technology-first methods.

The Centers for Medicare and Medicaid Services (CMS) continues to advance its interoperability goals and address process challenges related to e-prescribing and PAs. Proposed rule CMS-0057-P would require impacted payers to improve the electronic exchange of healthcare data and streamline PA processes.

Additionally, CMS continues to implement a provision of the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities (SUPPORT) Act that requires e-prescribing of controlled substances under Medicare Part D. Further, a recent Biden Administration proposal would implement e-PAs for several government insurer plans by 2026, as well as require payers and states to streamline PA processes and improve the electronic exchange of data. It also contains incentives for hospitals and physicians to adopt e-PAs.

While these regulatory changes will force many in the industry to adopt digital methods, the specialty pharmaceutical space may never fully transition to digital-only processes. Some may argue that the level of human intervention may always be needed, due to the complex nature of specialty product support. However, technology advancements within the space demonstrate that specialty is ready to embrace technology-first programs, or digital hubs. As noted ahead, the definition of a digital hub varies greatly by stakeholder.

A collection of technology-enabled solutions.

Electronic solutions available via web, app, etc.

But what a digital hub actually provides is much more specific (see graphic below). The source of confusion over the definition of a digital hub can be attributed to the uncertainty between “technology-first” and “technology-enabled” patient support programs. The first step to understanding a digital hub in 2023 is to identify how these two types of programs differ.

Understanding technology-first and technology-enabled solutions

Many patient support programs deploy technology-enabled solutions in some capacity, like electronic benefit verification (e-BV) or digitized enrollment. However, leveraging technology-enabled solutions does not mean the program is a technology-first program. The difference lies in the ability to automate the process with technology, versus relying on human intervention in the backend to prop it up.

For example, some patient support providers generate electronic benefit coverage via a combination of e-BV and phone calls to the payer, whereas technology-first approaches leverage direct connectivity with payers/pharmacy benefit managers (PBMs) to return comprehensive patient coverage results in real-time. Some providers utilize digital forms for PA completion. Technology-first PAs return the appropriate patient plan- and product-specific PA question set for completion and submission to the payer/PBM, with decisions returned in minutes.

A digital hub provider possesses two qualities:

The ability to integrate technology into all patient support services, fully automating the process, versus relying on human intervention to prop up technology.

A strategic choice to deliver services with a technology-first approach. This means every step of the patient journey that can be completed in an electronic, automated fashion begins and ends with technology.

Patient support providers that can deliver a digital hub must have advanced, interoperable technology, as well as an agnostic stance and willingness to integrate with all parties necessary to facilitate technology-first patient support.

Which products benefit from a digital hub?

Products that benefit most from a digital hub typically have some of the following characteristics:

Pharmacy benefit product at a stage in its product lifecycle in which most processes can be digital and automated.

Low wholesale acquisition cost (WAC) product unable to afford high-touch, full-time equivalent (FTE)-enabled specialty services or product approaching the loss of exclusivity (LOE) cliff.

Technology-savvy HCP population that is familiar with specialty drug processes.

Highly motivated, technology-savvy, and cognitively and physically able patient/caregiver population.

A payer mix of payers/PBMs with electronic capabilities.

Formulary position that does not require significant step edits and PA hurdles.

These products require little to no human intervention to maintain prescription journey momentum. Services can be completed in an automated fashion due to electronic connectivity and available data. Further, data required to make informed decisions, such as patient coverage information and PA requirements, can be returned with high accuracy through integrations, or direct connectivity, with the source.

It's important to note that the technology is only as good as the design. Digital hub program effectiveness depends on deploying the right technology at the right time and through the right delivery method. It’s critical that the digital hub vendor knows when and where to incorporate technology and talent not only throughout the product’s current therapy journey, but also as processes evolve along the drug's lifecycle.

For example, a high-volume, mid-lifecycle pharmacy benefit product with short PA approval periods would benefit from a technology-first (digital hub) approach, while a first-to-market, buy-and-bill product would need talent-enabled support at launch. However, a strong patient support program vendor supporting this high-volume pharmacy benefit product would likely have implemented tech- and talent-enabled support at launch to support HCPs with navigating payer hurdles and to drive perceived access. Talent would have also been leveraged to improve payer coverage by deploying payer-targeted product demand and clinical effectiveness call campaigns, and to evaluate when the program was ready to incorporate additional technology-first solutions.

How digital hubs impact patient and HCP experiences

 of HCPs under the age of 55 experience emotional distress and burnout in some part, due to the administrative burdens they face to ensure patient access. This realization underscores the need for digital hubs to support HCPs with simplified, automated processes. For example, digital hubs can incorporate a digital intake process that enables triggered e-support services at the point of e-prescription intake from the electronic health record/electronic medical record (EHR/EMR). This process automates and accelerates the therapy initiation process, while meeting HCPs where they are.

Digital hubs can support patients with managing their healthcare too, as many of today’s patients are familiar with digital processes. A recent survey reported that 

 have used telemedicine within their lifetime, and it's now the preferred channel for receiving prescriptions and care for some conditions. To meet patients where they are, digital hubs can incorporate omnichannel strategies, such as branded engagement websites, chatbots, and automated communications like text and email. However, these strategies must be designed and deployed in the right way for the product. A stratified, omnichannel approach based on patient segmentation yields the best results, as patients can self-serve, engage with the brand through a variety of channels and do so at their convenience.

Further, digital hubs should stratify patient populations based on adherence risk to deliver tailored technology-first and talent-enabled adherence solutions based on the patient’s risk profile and communication preferences.

HCP segmentation is needed for a successful program, too. It is essential for digital hubs to not only stratify HCP populations to meet them in their workflow, but also to identify which offices require additional support. For example, a PA denial due to a missing letter of medical necessity (LMN) for a less-technology savvy office would trigger a different follow-up task than a technology-savvy office that receives a PA denial for the same reason. The first office would receive a triggered fax containing the appropriate template LMN. The second office would receive a triggered email containing a tokenized hyperlink to complete the LMN/e-appeal.

Delivering differentiated experiences with a digital hub

Digital hubs can create tailored technology-first experiences for program stakeholders that differentiate the program in a competitive market. To remain competitive, program design must evolve with the product lifecycle, HCP technology adoption, and patient life stage/disease progression. Let’s review a few examples.

Electronic benefit coverage results generated via e-eligibility or test claims.

What a technology-first approach would look like: 

A solution that delivers comprehensive electronic benefit coverage results generated via direct connectivity with payers/PBMs and other data sources.

How this technology-first approach differentiates a program:

 Provides accurate and comprehensive coverage results in under 15 seconds.

Digital presentation of a PA form submitted to the payer/PBM through e-fax.

An end-to-end e-PA solution that generates the digital product- and patient plan-specific PA question set, facilitates real-time submission to the payer/PBM through direct connectivity, and returns PA decisions within minutes through this same connectivity.

Deciphering the different "technology-first” and “technology-enabled” patient   support programs.

Pharmaceutical Commerce - April 2023

Pharmaceutical Commerce - April 2023 Issue (PDF)

Keeping Up with the Action

Assessing Drug Pricing in Europe

Pediatric Medicine: Challenges Abound

Ramping Up DSCSA Readiness Efforts

High-Tech Hubs and Specialty Pharma

What is a Digital Hub in 2023?

Patient Hubs in an Omnichannel World

Solving the Omnichannel Puzzle