In a world where health systems are increasingly focused on value-based pricing and personalized treatments, the heightened emphasis on scientific exchange between the pharmaceutical, biotech, medical device and diagnostic industry and its customers has never been greater. The perception that the sales representative is the sole interface between industry and healthcare providers (HCPs) is actually changing, with growing importance being placed on the role and functions of medical affairs. As a result, medical affairs teams, responsible for interacting with physicians and payers about scientific publications, off-label usage, product safety and independent medical education, have seen staggering growth in recent years. [1] At the heart of this shift sit the medical science liaisons (MSLs)—highly qualified personnel, often PhDs or MDs, who help communicate product-related science to prescribers, key opinion leaders (KOLs) and payers.

While this shift has been welcomed by health systems, who thirst for the scientific knowledge necessary to remain patient-centric, the challenge is to remain vigilant of promotional compliance regulations. Medical affairs teams must maintain a respectful distance from traditional sales and marketing functions, a point noted in early guidance emerging in 2003 from the HHS Office of Inspector General (OIG), which clearly stated that grant funding from pharmaceutical manufacturers must remain independent from physician referrals for medical products. [2]

At the same time, increasing pressure has been placed on the life sciences industry in relation to promotional compliance, including transparency around traditional sales and marketing activities with HCPs through measures such as the US Physician Payments Sunshine Act (2010). This regulation, which is reflected in similar legislation in other markets, requires life sciences companies to log, track and report on HCP spending. As a result, physicians are reacting by exercising increased caution when participating in engagements with industry, in particular when there is any kind of compensation. For example, in December 2013 GlaxoSmithKline announced that it would stop compensating HCPs for speaking on the company’s behalf regarding its products and related disease areas, and would in fact rely on its own internal experts to communicate with disease-area experts, potential prescribers and other HCPs. [3]

First announced about a year ago, Zephyr Illuminate is of a category of IT solutions that the company, and some others [1], call “insights as a service;” whether this moniker will hold remains to be seen. At its heart, Zephyr Illuminate is a combination of patented, machine learning algorithms that create predictive insights using global health data for major treatment areas from thousands of connected data sources—public, private and vendor-sourced. These Big Data techniques—operating on a cloud-based platform—produce meaningful results (“insights”) for such questions as, which healthcare providers (HCPs) or healthcare organizations should a company target for a medical education campaign? How can a target customer or market be segmented to improve commercial performance through increased customer engagement? What communication channels are most effective with which customers? Which HCPs or KOLs are industry up-and-comers? All in the spirit of improved data-driven targeting and deep customer profiles.

According to Zephyr, the system can be set up in a transparently compliant manner so that medical affairs personnel and sales personnel have a shared view of customers, yet have defined viewership of information based upon their roles, e.g., claims or sales performance data is not available to a medical affairs user. Patient data, when part of the database, are de-identified and HIPAA-compliant.

1) See Vendor Landscape: Insights Service Providers, May 2016, Forrester Research

The cost of incorrect reporting is significant; whether the misdemeanor is intentional or not, there are financial and reputational risks. For example, unintentional failure to report a transfer of value to an HCP can cost a manufacturer a fine of $10,000 for each individual transfer of value, up to a maximum of $150,000 annually. If a manufacturer is thought to have knowingly held that information back, then the possible fine increases—up to $100,000 per infraction up to a maximum of $1 million. These sums might seem small to a multinational, but in addition to the cash sums, punishment for knowingly failing to submit reporting data can result in the OIG imposing a corporate integrity agreement on the manufacturer.

Market pressures and heightened focus on transparency and compliance, combined with the exponential growth of publicly accessible data sources, have created unique challenges for medical affairs teams, given its responsibilities in scientific data generation and dissemination.

As with many changing market dynamics however, these also represent an opportunity within life sciences companies for better planning and execution of their strategic programs, while ensuring compliance. Now more than ever, Medical Affairs teams can lead their scientific initiatives with fact-based insights by integrating their internal tracking systems with the growing set of external data sources available to them to ensure a clear audit trail of activity and to meet regulatory demands. Whether in the selection process that identifies KOLs, prescribers and payers, or their recorded interactions, new technology solutions provide an increasingly transparent, objective and compliant way to better manage data across an entire organization.

In view of this, there are three exciting opportunities for medical affairs teams to address these challenges and transform their initiatives with fact-based insights:

 Identification and management of   thought leaders

Alignment of home office and field based initiatives

 Measurement of medical affairs activities

Despite advances in access to data, it is still difficult for life sciences companies to identify and engage with thought leaders using objective, up-to-date and integrated data sets. This is due to the difficulties in aggregating disparate data sources—internal or purchased. In particular, 80% of publicly available global health data is unstructured, [4] which presents unique challenges for integration.

For Medical Affairs this means that researching and identifying new thought leaders is more often based on anecdotal feedback from the MSLs, or time-consuming online searches, and less on objective and quantifiable data. Furthermore, understanding more about the connections between these thought leaders and the institutions where they work, as well as the other healthcare providers they work with, is arduous to ascertain. Detecting changes or updates to healthcare provider or organization profiles is even more challenging over time. For instance, getting updates on recently published articles or participation in new clinical trials, or even understanding an HCP’s engagement with a competitor can be taxing and time consuming.

In fact, according to two recent Zephyr Health engagements with top 10 biopharma companies, it was estimated that MSLs spent between 20 and 30% of their time researching and profiling thought leaders. The results of ad hoc searches to locate such information are frequently tracked in Excel sheets or in individuals’ files, making consistency and compliance questionable. This makes it challenging for therapeutic area heads to validate proposed thought leader candidates lists, develop key account engagement plans and perform MSL territory planning with confidence, especially if he/she does not know  the candidates.

Next-generation technology solutions are helping to reshape Medical Affairs thought-leader programs by providing a systematic and objective way of identifying thought leaders and institutions. The integration of public global health data, third-party licensed and internal data into a single holistic view means medical affairs teams have up-to-date customer profiles and can extract relevant and immediate insights on key thought leaders, accounts and institutions. Thought leader engagement and medical education programs can be transformed by having the right information to share with the right customer, at the right time in a compliant manner—meeting the need to disseminate critical science to key stakeholders, while enhancing credibility and corporate reputation.

Identifying and populating the information gaps from MSLs’ anecdotal knowledge of key customers is one challenge—effectively recording their activities and sharing field insights with home office is another. While sophisticated customer relationship management (CRM) systems are now routine for field-based personnel, information found within emails, voicemails and personal notebooks may not always be recorded. Even when it is, it can get lost in translation to medical affairs managers, therapeutic area heads and medical directors, which limits market insights and poses significant compliance risks. A further example is the management of payments to KOLs for speaking engagements, a company might already have the physician’s details, records of travel expenses and speaking services provided, but the payment details themselves—the date the payment is made for instance—are very likely only available on a separate accounts payable system.

Many companies have established firewalls between medical affairs and commercial functions, in addition to implementing corporate integrity agreements, to ensure regulatory compliance, but two key challenges remain. First, the lack of direct communication between medical affairs and sales means there are often inconsistent views of the same customer, which creates inefficient engagement processes and frustration for HCPs. Second, and more important from a compliance aspect, failure to separate medical affairs and commercial activities can pose a significant risk in the face of external audit. For example, Allergan was required to make a $600m settlement in 2010 after failing to separate promotional and educational activities in relation to its blockbuster drug Botox. [5]

Innovative technology solutions are helping life sciences companies align external and internal information into a single, synchronized view of HCPs and their related institutions or organizations. Sales and medical affairs activities can be closely monitored and insights shared across all divisions of the company in a compliant manner thanks to user and role-based access, which allows for a clear separation between medical interactions and sales engagements. For example, sales teams can only see HCP and institution profiles in their assigned territory and cannot view any medical interactions data.

Similarly, medical affairs teams can view research and medical interactions data but are restricted from seeing prescription volume or sales interactions information. Marketing teams can see all commercial interactions data to drive brand strategy but have limited access to medical interactions data. These roles and defined viewership can be tailored for each company, meeting specific company-based compliance requirements.

By better connecting home office and field-based personnel with both web-based and mobile solutions, medical affairs can optimize strategic planning and gain real competitive advantage. MSLs have visibility of, and learn from, collective experiences with customers, while headquarters can react more nimbly to changes in the external market, all while ensuring regulatory compliance.

With an accurate view of thought leaders, KOLs, HCPs and institutions and alignment between home office and field-based activities in place, the final challenge for medical affairs is in measuring the performance of its activities, both for communicating benefit to senior management and for providing appropriate incentives for personnel.

Proving the value of, and providing the right performance incentives around medical affairs initiatives and actions is a constant battle as measuring the success of programs cannot be directly linked to sales and revenue, for exactly the reasons stated above. Innovative metrics must be developed to meet this challenge and, most importantly, stand the compliance test. Key performance indicators often include the number of calls a medical information center receives or number of KOL relationships per MSL. These can provide insight into the level of productivity, but relay little about how impactful specific programs are.

Here again, technology is a key differentiator, aggregating statistics and data to efficiently track the progress of initiatives over time. By deploying next-generation data aggregation and insights solutions, medical affairs teams can measure the relative performance of HCPs across multiple categories such as research, influence, engagement and more. For example, measuring the change in a customer’s sentiment, involvement in trials or authorship of new publications, specifically in relation to company-sponsored products, is now possible and provides a tangible way to monitor the impact of medical affairs’ activities.

With objective measures of performance, medical affairs teams can quickly and easily relay the impact of  their initiatives to those therapeutic  area heads and senior managers who have a view across medical and commercial activities, allowing them to track the  impact of all functions. This allows development of more credible strategic plans and better allocation of resources, while also ensuring appropriate, compliant rewards for those involved in deploying effective medical programs.

Changes in the healthcare environment have led to the growing importance of medical affairs activities, while a concomitant tightening of the regulatory environment for life sciences companies, including measures like the Sunshine Act, means such activities must be more closely monitored and measured. Transparency around engagement with HCPs is clearly here to stay and it is forcing the industry’s hand when it comes to capturing data and delivering insights.

Populating information gaps and integrating data across the business are the key areas that companies must address for successful and compliant implementation of medical affairs activities. Disparate data sources within an organization are a significant challenge, and integrating those systems is no small feat. This point is highlighted no better than in research conducted by SAP, which concluded that a life sciences company could have HCP spend transactions originating from as many as 20 different sources and systems. [6] Mistakes made because of fragmented data can have costs that far outweigh the transfer of value in dispute.

With next-generation technology, life sciences companies can now benefit from a single-point solution that aggregates data and tracks spend—and that provides the analytical insight to build up  HCP and institution profiles, monitor the success of interactions with them,  and ensure compliance by separating medical affairs and commercial activities. With such systems, the industry can transform thought leader and medical education programs using consistent, fact-based solutions, while also meeting compliance requirements. The more relevant and appropriately aligned interactions the industry has with  HCPs and thought leaders, the more  they build trust and better relationships with consumers and the medical community at large.

Medical affairs will play a vital role in the future success of the life sciences industry. Those companies investing in the right solutions to empower their medical affairs teams with insights will develop better customer relationships and gain significant competitive advantage—their future will be insightfully compliant.

Focus on Life Science Compliance: The Evolution of Medical Affairs Departments (2011), McGuireWoods LLP, accessible at 

https://www.mcguirewoods.com/news-resources/publications/health_care/focus-life- science-compliance-nov-2011.pdf

Pharmaceutical Compliance Guidance Program for Pharmaceutical Manufacturers, Apr. 2003 (68 Fed. Reg. 23735 [May 5, 2003]), accessible at 

http://oig.hhs.gov/authorities/docs/03/050503FRCPGPharmac.pdf

GSK Announcement May Change Industry Speaker Programs (2014), Law360, accessible at 

http://www.law360.com/articles/505701/gsk-announcement-may-change-industry-speaker-programs

Five Things You Never Suspected About Your Healthcare Data (2015), Forbes, accessible at 

http://www.forbes.com/sites/robertszczerba/2015/08/19/five-things-you-never-suspected-about-your- healthcare-data/#4626

Allergan Will Pay Fine, Plead Guilty to Misdemeanor (2010), Bloomberg, accessible at 

http://www.bloomberg.com/news/articles/2010-09-01/allergan-will-pay-600-million-plead-guilty-to- misdemeanor-in-botox-probe

 SAP White Paper—Engaging the Healthcare Practitioner (2010), SAP, accessible at 

http://www.sdn.sap.com/irj/scn/go/portal/prtroot/docs/library/uuid/c06c7336-6195-2d10-b18b- 94527b9196a9?QuickLink=index&overridelayout=true&48747879804892

William King is the founder and executive chairman of Zephyr Health; the Insights-as-a-Service leader harnessing the power of global health data to help pharmaceutical, biotech, medical device and diagnostic companies engage the right physicians, accounts and institutions. Prior experience includes global leadership positions in sales, marketing and strategy at Johnson & Johnson. His bachelor’s degree in business administration is from the University of Denver.

Articles

Technology is enabling more resources to reach the medical  affairs teams—in a compliant manner

Powering up medical affairs

On first hearing what’s been going on in the disputes between brand drug companies and their generic competitors over obtaining samples for testing, the initial reaction is, here’s an obscure digression from the grand process of drugs going off-patent, who cares? After all, generics constitute around 90% of US drug prescribing; blockbuster drugs routinely go off-patent and both the innovator pharma companies and the generic competitors are getting by. The grand Hatch-Waxman compromise between the two, although much amended over the years, works.

Nevertheless, this dispute has been dragging on for years and shows no sign of resolution. Yet another Congressional hearing was held (the Senate Judiciary, in late June) and another bill, the Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act (S. 3056)* has been introduced; FDA took one stab at correcting the problem (which mostly hasn’t worked), and the Federal Trade Commission has gone back and forth on whether to invoke antitrust rules. The issue is burning up time and resources at FDA and among pharma companies that would be better spent on more pressing matters.

The problem, in a nutshell, is that generic companies need samples of branded drugs in order to perform the bioequivalence studies to gain FDA approval. But some branded companies make it very difficult for the generic firms to obtain them (even though the drugs are in commercial distribution, and even though a legitimate sale and a fair price could be agreed to). Even more sand is thrown in the gears of progress when the branded drug is approved with a Risk Evaluation and Mitigation Strategies (REMS) program, which requires additional safeguards for how the drug is to be dispensed to patients. Months can go by in frustrating negotiations and litigation. The Generic Pharmaceutical Assn. puts a more-than-$5-billion cost on this disputation. Money is wasted, action is delayed and the goals of Hatch-Waxman are undercut.

There appear to be three distinct situations leading to the delays:

 When a branded drug company has a closely controlled distribution system enabling it to simply choose whom to sell to;

When a drug has a REMS program, and the branded drug company invokes the terms of REMS program to “protect” clinical trial patients;

When the details of the REMS program are claimed to be patented intellectual property (IP), and not to be shared.

Antitrust and IP lawyers have feasted on the intricacies of the legal issues that can be invoked here, but my point of departure is very simple: getting the samples to conduct a study is not an automatic path to approval; it’s the rules of the game as defined by Hatch-Waxman. Refusing to provide samples is the little boy who takes his baseball and bat away from the playground because he can’t hit a home run. It’s petty and a little sleazy.

The REMS factor is more complicated, but the point I would make is that the original intent of REMS regulations was to speed the approval of drugs that had potentially dangerous side effects; manufacturers and FDA regulators agree on how to address those risks with follow-up attention after the drug is on the market. (More than a few REMS programs have been dropped after commercial use showed a potential risk was not an actual one.) Using REMS to block generic development is a subversion of that original intent.

There are legitimate reasons to have restricted or exclusive distribution agreements, especially for specialty pharmaceuticals for which patients benefit from extra attention and support. The danger here, for branded pharma companies, is that restricted distribution is an opportunity for abuse, as the infamous Turing Pharma situation of last year demonstrated. PhRMA (and others) who have supported the current bioequivalency-study obstacles run the risk of further poisoning the public perception of restricted distribution, which in turn could throttle the patient support the programs provide.

https://www.congress.gov/bill/114th-congress/senate-bill/3056/text

Enough already with REMS abuse in generic drug development

One of the attributes of the burgeoning specialty pharmaceutical market in the US is that many of the products are moving through distribution channels via nontraditional channels. Part of this is due to their very nature—they often require special handling (such as temperature-controlled, refrigerated transportation and storage). Part of this is due to the growth of alternative sites of dispensing—infusion centers, outpatient clinics and most of all specialty pharmacies (SPs), a rapidly growing category of retail pharmacy. But the most fundamental reason, it seems, is the combination of financial and business-relationship arrangements between manufacturers, payers and providers that, in some cases, affords better opportunities to access the market for manufacturers, and cost savings or streamlined operations for payers.

The most notable example of this is direct distribution—going from the manufacturer direct to the practitioner’s office, or even direct to the patient. Products that need to be compounded or customized for patients might stop at an SP along this route, especially in cases where the SP provides additional services to patients to support their care. This has led to the rise of limited or exclusive distribution networks, where a specialty drug is available only through one or a few SPs, who in turn serve local, regional or national markets.

Whichever pathway a specialty drug takes along its route, the key service providers are third-party logistics firms (3PLs). The 3PL business is not unique to specialty drugs, or to pharma generally—it exists for a wide range of businesses and industries. The defining characteristic of 3PLs is that they act as the product owner’s agent, arranging storage and transportation of the product, often including receiving and fulfilling orders, and managing payments—but not taking ownership of the product (except, paradoxically, when they do—more about that later).

Specialty logistics and distribution is a good business to be in these days, simply because of the strong growth of specialty products coming out of pharma labs and factories. IMS Health, in its annual Use of Medicines report, pegged the 2015 specialty market at $150.8 billion and representing 75% of new brand spending growth. That figure is up 21.5% from the previous year (IMS cautions that this invoice price does not include the discounting that occurs with different types of buyers). Specialty drugs tend to be the newer types of biologics, oncology products and the small but lucrative drugs approved for rare diseases.

Nearly all of the major US wholesaler-distributors have a 3PL service offering; it’s fairly straightforward for them to complement their national distribution and transportation services for the products they buy with 3PL services operating alongside the wholesaling business. At Cardinal Health Specialty Solutions, VP/GM Jennifer Fillman notes that the unit is growing at a double-digit rate and is projected to be an $8-billion business within Cardinal, according to its FY2016 results (this includes all specialty services, not just 3PL).

The company has developed a 3PL service that showcases the value of this arrangement for manufacturer clients. Called the Exclusive Pharmaceutical Transportation Network (EPTN), it comprises a central warehouse in La Vergne, TN, with dedicated shipping lanes that can cover 75% of the continental US with ground transportation and 48-hr delivery. Manufacturers deliver pallets to La Vergne; Cardinal Specialty Services combines shipments from diverse manufacturers but going to the same destination and sends the products on their way. All of the shipments are made with refrigerated trucks, ensuring temperature control of cold chain products. Destinations include wholesalers, central pharmacies of hospital networks, and SPs that handle national dispensing.

“By consolidating shipments from multiple clients, we can reduce transportation costs while also eliminating many of the touchpoints of handoffs or transfers of conventional less-than-truckload delivery,” notes Fillman. “This has had a substantial impact on the volume of products that are returned for credit because of damage during shipping.” Fillman says that manufacturers routinely come to Cardinal Health Specialty Solutions with that specific goal in mind.

The journey of a specialty pharmaceutical delivery varies once EPTN has made its deliveries. SPs, shipping to individual doctor’s offices or patient homes, might repack the shipment in its own temperature-controlled container and then use an air carrier like FedEx or UPS to make an overnight delivery. Shipments to hospital central pharmacies move between one healthcare facility or another. Shipments to full-line wholesalers might wind up going to regular local pharmacies (for manufacturers putting the specialty drug in open distribution), or enter the specialty network handled by that wholesaler.

Cardinal Health Specialty Solutions, like other 3PLs, also handles order-to-cash processes for the manufacturer; this is fairly routine, but can entail some complexity when a “drop shipment” occurs. Drop shipping is the term used in logistics to describe a delivery made by one party on behalf of another; in this case, the manufacturer might be drop shipping directly to an SP customer, but lacks a business relationship with that customer. Even though Cardinal Specialty didn’t handle the delivery, it has the business relationship with the customer, and so completes the order once notification is received that the delivery has been made.

Another financial aspect of 3PL services is when they agree to “take title” (effectively, buying) the product. There are reasons to do this, as opposed simply to having the manufacturer sell to wholesalers as in conventional distribution. The manufacturer wants to take advantage of the dedicated specialty services in delivery and handling, but doesn’t have the appropriate licensing in place for national distribution (a growing number of states require drug providers to have a license, and the rules continue to evolve). Many 3PL providers, including Cardinal Health, RxCrossroads and other 3PL providers mentioned in this article, have the necessary licensing, and so can step in to make compliant deliveries. The practice is especially useful for emerging pharma companies who either don’t have all the state licenses in place, or who rely on their 3PL partner for the service.

As a business serving high-volume specialty products, this 3PL activity was pioneered by AmerisourceBergen, which set up its Specialty Group in the early 2000s and maintains some key company brands, such as ICS, Oncology Supply and US Bioservices, to this day. Like Cardinal Health, McKesson has a Specialty Health Solutions business unit; it absorbed a network of community oncology centers, then known as US Oncology, several years ago. H. D. Smith and other full-line wholesaler-distributors also provide  3PL services.

A second tier of 3PL providers are companies not part of a full-line wholesaler, but providing dedicated specialty 3PL services nonetheless. A major player here is RxCrossroads, which, as part of Omnicare, was acquired by CVS Health less than a year ago. Rob Brown, VP of business development, says that the focus for his company’s 3PL services are smaller manufacturers that lack the internal resources to manage a national distribution process (or choose to invest their resources elsewhere) but need the high-touch services RxCrossroads will provide. Generally, clients ship pallets to RxCrossroads two central warehouses in Louisville, KY, and the shipments are either sent direct to wholesalers, or broken down to cartons or individual packages for delivery to hospitals and clinics. RxCrossroads has extensive experience in cold-chain delivery; the company can repack the shipment, per the manufacturer’s requirements, and then pass them on to an express carrier for overnight delivery. “Most of this repackaging is a customized service; some packouts can be very complex, with as many as 10 components specified for each container,” he notes.

RxCrossroads, as it happens, is the leading provider of 3PL services involving collecting blood plasma from donation centers around the country, storing those shipments for up to 60 days (an FDA requirement), and then delivering them to the handful of firms that fractionate blood plasma into albumin, immunoglobulin, coagulation factors and other prescribed products (Pharmaceutical Commerce, March/April, p. 20). Generally, the raw plasma is shipped and stored frozen, and RxCrossroads has a dedicated fleet of refrigerated trucks to handle the collection. Once stored, however, follow-up verification of donors’ suitability can necessitate going into the inventory and removing some donations, to prevent cross-contamination problems when the plasma is later processed. RxCrossroads also handles some of the downstream delivery of these blood products (as it would other specialties).

As to trends in specialty distribution services, Brown says there’s a movement among healthcare providers to set up “buy and bill” arrangements with manufacturers. Buy and bill has been a traditional practice in community oncology; the oncology office purchases (and keeps on hand) a limited amount of oncolytics, and then bills payers for dispensing them to patients. The practice is expanding in recent years to dermatology, hematology and some of the growing number of rare disease therapies.

For the manufacturer, the 3PL services from RxCrossroads enables it to avoid the complexity of order management with diverse, small customers. More generally, many manufacturers are seeing advantages in the specialty 3PL arrangement as part of a larger process of engaging the specialty distributors’ hub or patient support services, as a means of managing the drugs’ commercial distribution better. “Many of our 3PL clients take advantage of the patient support services that RxCrossroads provides,” says Brown.

The CVS Health/Omnicare/RxCrossroads connection will eventually lead to some cross-functional business among the units (CVS Health is a major specialty pharmacy in addition to its retail business), but for now, Brown says, the business is still running its own network. The new corporate parent has committed to a major expansion of the Louisville facilities, with groundbreaking not yet announced.

High-touch 3PL services are also available from other firms, including LifeScience Logistics, BDI Pharma, MD Logistics, and, to a degree, from the major international logistics providers such as UPS, FedEx and DHL. FedEx opened a cold chain center earlier this year to handle its increased volume of temperature-controlled products; the company also has its Custom Critical subsidiary, which handles specialized service deliveries of pharmaceuticals and other products with a dedicated fleet of refrigerator vehicles.

In May, LifeScience Logistics announced that it had received ISO 13485 certification, enabling it to assure medical device manufacturers of the quality controls it maintains. The company is also in the process of expanding its Brownsburg, IN facility.

Other distributors pick up specialty business where they can, when the combination of the client needs and their own capabilities align. At Woodfield Distribution (WDSrx), the company began working with a women's healthcare product manufacturer in 2012. By leveraging its financial management services, its on-site call center for physician outreach and its core pharmaceutical warehousing and distribution capabilities, WDSrx managed the entire sales and service process for their client from initial online ordering through fulfillment to individual addresses, invoicing and customer service including returns.

According to WDSrx President Adam Runsdorf, "The omni-channel business model originated as a hybrid of several of our core and value-added services. Our experience with pharmaceutical drug products places WDSrx at the center of potentially significant changes that may open a new distribution channel from manufacturer to final destination.”

With some specialty drugs, especially those for rare diseases, it can be difficult to define where clinical trial development leaves off and commercial distribution begins. This blurring has been highlighted by the recent attention FDA has paid to what it calls “expanded access” for drugs under development, whereby patients and their physicians can apply for use of the drug prior to formal approval. For that reason, as well for the inherent capabilities of the clinical trial logistics firms, there is some movement toward using those firms’ networks for specialty distribution.

World Courier, a leading clinical trial logistics provider, is moving in this direction, having expanded the capabilities of its depot in Melbourne, Australia (which was set up originally for clinical trials management in the Southeast Asia region) to include commercial distribution. The arrangement, announced in early 2015, “is progressing nicely; we’re filling up our commercial capacity and proving our hypothesis that this can work for clients,” says Doug Cook, president of Global Specialty Logistics at AmerisourceBergen.

One driver for this business is that it enables World Courier (and its parent, AmerisourceBergen) to move smoothly from clinical trial services through to commercial distribution once a drug is approved. But another reason is simple economics: for firms that are putting a toe in the water to market products globally, it’s a way to start on a smaller scale and build up a market for its drug.

The mechanics of the conversion can be fairly straightforward: the company already has resources in place to handle cold chain products, to perform repackaging or kitting, and has the necessary licenses for commercial distribution (Cook says that the majority of the company’s 13 depots outside the US are already licensed for commercial distribution). “We’re built for the more complex distribution situations; it’s our sweet spot,” he says.

Looking ahead, Cook sees his company’s services being a vital part of the coming era of personalized medicine, especially cell therapy-type drugs that might involve cells from an individual patient, being processed in some manner in a lab, and then returned to the patient for infusion. “We’re already working with more than half of the clinical trials involving gene therapies, and almost half of the companies working on cell therapies,”  he says.

World Courier’s arch-rival, Marken, is also active in this area. The company has expanded its global network (most recent openings include Boston, MA and Moscow, Russia), as well as to expand its network of partner logistics providers to enlarge  its capacity.

Managing the physical movement of specialty drugs calls for dedicated services

3PLs set specialty pharmaceutical markets in motion

By all counts, the global pharma traceability initiative—driven by the Drug Supply Chain Security Act (DSCSA) in the US, and the Falsified Medicines Directive in Europe—is moving ahead, with equipment and software contracts being placed, and project managers getting to work on implementations.

There is a core group of companies that have been carrying along traceability work since the early 2000s, and have lived through the lean days after California dropped its “electronic pedigree” deadline of 2008, and then bloomed again after DSCSA was passed in late 2013. (While most serialization and traceability work is driven by regulatory mandates, all along there have been pharma companies deploying traceability solutions to meet business needs). Now, companies like TraceLink are touting a doubling and redoubling of staff at its new headquarters in North Reading, MA; Optel Vision, a provider of packaging-line visibility solutions, has added several hundred staff and opened a center in Europe, and Systech International has also opened a new headquarters and is building up both its domestic and international business.

Barcode-marking and machine-vision equipment providers like Domino Amjet, Videojet, Cognex and others are seeing a pickup in business from pharma. Industrial automation vendors like Rockwell and Siemens are incorporating traceability work into their overall industrial automation business. Some combined equipment and software companies, like Mettler Toledo and its PCI Services unit, are in the fray. Companies with a strong base of traceability business in Europe, such as Antares Vision and Adents, have opened US offices and supply centers.

Some recent news announcements from these and other vendors:

Verizon Enterprise Solutions, which provides broad-based communications services to corporations, has partnered with rfXcel, one of the longtime traceability software providers, as the foundation of Verizon’s Intelligent Track and Trace offering. The unusual pairing (most traceability vendors specialize in what amounts to a niche in the overall enterprise IT field) makes sense when FDA settles on a guideline for how pharma companies and their trading partners are to manage the massive data-handling burdens of commercial drug distribution under DSCSA.

Acsis, a provider of “edge solutions,” specifically for managing the coordinated flow of data from a packaging line, into and out of a warehouse, has announced winning the business of American Health Packaging (a unit of AmerisourceBergen that repackages drugs, typically for hospitals). Data in the warehouse will be captured with scanners and then stored as events in a DSCSA-compliant database; AHP says it will realize time and effort savings in shipping-related processes. The application includes printing shipping labels from the stored data.

TraceLink is partnering with ROC IT Solutions, another edge-solutions provider, to extend traceability functions into the warehouse and beyond. ROC IT’s EdgeTRAC and TraceLink’s serialization solutions are already live in production together, notes Larry Hall, ROC IT founder, “demonstrating the simplicity of the system integration and sub-second response times between the EPCIS repository and the edge system.” (EPCIS is the acronym for the serialization standards promulgated by the GS1 organization, and are the de facto standards for DSCSA compliance.) “We’re excited to partner with TraceLink and tap into the largest global sales team that is exclusively focused on track and trace for life sciences, which will enable us to accelerate worldwide adoption of ROC IT solutions across the industry," adds Hall.

Almac Group, a sizable contract development and manufacturing organization (CDMO) based in Northern Ireland, had built its own serialization solution for operations there, but has chosen Optel Vision for a US implementation. “To expand the solution into our US operations, we decided that we needed an experienced partner that could integrate with our innovative product-serialization site-level software,” said Grainne Hughes, Almac operations manager. “The partnership with Optel Vision has provided our US commercial packaging facility with a truly flexible and adaptable solution to readily meet specific country, market and client requirements whilst ensuring serialization to GS1 Standards.”

Adents, now with a New Jersey US HQ, has announced partnerships with LMN Services, a North Carolina-based systems integrator for pharma, and with Clarke Engineering Services, a manufacturing and packaging technology solutions provider, for Adents software implementations. Adents, according to James Cummings, VP Americas, emphasizes open-standard implementation of its software.

Systech International has announced two partnerships with equipment vendors Omega Design, which manufactures a range of materials-handling and marking equipment in pharma and consumer healthcare; and Etipack, a global labeling and coding equipment supplier based in northern Italy. In addition to UniSolve offering for traceability, Systech has been actively marketing UniSecure, its proprietary technology for authentication of packages.

 Recipharm, a contract development and manufacturing organization (CDMO) in Jordbro, Sweden, is deploying packaging line equipment from Marchesini, the Italian producer, machine vision technology from SEA Vision, another Italian company, and enterprise traceability software from TraceLink across its network of 15 plants in Europe, representing more than 75 production lines. The company already provides serialized product in Turkey, China and South Korea (countries that have had mandates comparable to the US’ and EU’s). “At an early stage, we took the decision to lead the market and make a significant investment into state-of-the-art solutions to actively help pharmaceutical companies meet new drug serialisation requirements,” said Staffan Widengren, Recipharm director of corporate projects.

Arvato Systems, a business unit of Germany’s Arvato supply-chain management company, is partnering with Systec & Services (not to be confused with the US’ Systech) to perform implementations of Arvato Systems’ CSDB (Corporate Serialization Database) solution. Both are major pharma IT players in Europe; CSDB is the designated solution platform for the traceability initiative of the European Medicines Verification Organisation (EMVO), which is coordinating industry response to the Falsified Medicines Directive.

The most active part of the serialization mandate at the moment in the US is equipping packaging lines to provide item-level serial codes; these codes need to be in place by November 2017 (deadlines for actually using the codes to confirm shipments comes later). All major pharma manufacturers are engaged in this activity; but there remain worries about the energy that CDMOs are dedicating to the effort—ultimately, someone is going to have to code the packages coming from the CDMOs if they themselves are not so equipped. The serialization effort has also been going on with distributors and logistics providers; if they do repackaging for a client, a code will need to be generated, and even if they don’t, they’ll need the system in place to receive serial code information and store it for use by downstream customers. Major CDMOs like Sharp Packaging and PCI (along with above-mentioned Almac) have been public about their efforts. Distributors like Woodfield Distribution and LifeScience Logistics have also announced their implementations. “This is not a trivial investment,” notes Richard Beeny, president of LifeScience Logistics.

And while it’s hard to define where the hardware costs are in relation to the software costs, the latter tend to draw significant attention from market analysts and consultants, perhaps because the implementations are a relatively complex undertaking with uncertain outcomes.

IDC Health Insights, one such market analyst, published a report this spring (see figure) giving a snapshot of where the leading enterprise traceability vendors are, and assessing TraceLink, Axway and rfXcel as market leaders. IDC analysts note that SAP has made a major foray into the market with Advanced Track and Trace, a dedicated IT solution specifically for DSCSA and FMD compliance, but that industry experience in implementing and using the technology  is still being developed. “It’s a snapshot,” says Michael Townsend, IDC research manager, noting that that market is very fluid at the moment and will continue to evolve as the regulatory mandates  get closer.

As the pharma industry moves ahead with traceability initiatives, vendors are building their capabilities

In the track-and-trace trenches

The category of enterprise quality management software (EQMS) has been around for quite a while, and managers in clinical trials, plant manufacturing and laboratories have been accustomed to employing these systems to collect data, organize it, and manage documents. A more recent application is now coming on strong, says Matt Lowe, EVP at MasterControl (Salt Lake City, UT), one of the leaders in this space: good distribution practices (GDPs), especially as the recently enacted European Union GDP standards propagate through the global pharma industry.

“Quality systems are traditionally managed within each functional area of an enterprise—clinical, manufacturing and so forth,” he says. “Distribution management is fairly new to this activity, and the advantages of an enterprise system are not well understood.” The company has done two things to broaden its platform’s appeal: a just-announced new user interface that improves interaction with the software; and, in the past year, a scaled-down version of the software called Spark, specifically for small businesses or dedicated functions within an enterprise.

EQMS systems serve to provide a centralized process to collect necessary documents, signatures and data to verify that a quality process has been maintained (including signatures that comply with FDA’s 21 CFR Part 11 requirements, which ensure that signatures are authenticated); a key function, often poorly managed, is documenting corrective actions. Lowe says that the bigger, global logistics companies serving the pharma industry have been using EQMS systems for a while now, but GDP standards are broadening their appeal.

The growing compliance requirements for distribution call for  a streamlined approach

Consider enterprise quality management systems for  GDP tasks

Lisa A. Butler, newly elected president of the PDMA Alliance, has been an Alliance Board Member for the past three years. She is an associate director of DEA/PDMA Compliance for Novartis Business Services. For the last 25 years, she has held various positions in the pharmaceutical industry and has worked within her current area of responsibility for the last 15. Lisa’s areas of expertise include: DEA Controlled Substance compliance, PDMA Sample Compliance and State and Federal commercial distribution licensing for pharmaceutical products.

Alliance Past President" alignment="right"/>

Lisa takes over from Don DeSmet, Alliance President for the past three years. He has served on the Alliance Board for 12 years. During this time, Don’s steadfast leadership, dedication and his ability to bring people together have been an inspiration to his colleagues. Working at Bayer Healthcare for 15 years, Don is now Manager of Sample Accountability, responsible for PDMA compliance, as well as Vendor Partner Management for Sample Accountability and Bayer’s Sample Send program. Previously, Don spent 25 years in various senior logistics and warehouse operations positions for both pharma and consumer goods organizations.

Changing of the guard at PDMA Alliance

Having the privilege to serve  on the Alliance’s board affords me an enormous and gratifying experience, highlighted by the opportunity to participate in developing a new conference program each year. From the end of one year’s conference to the next, board members are diligent about foreseeing and planning a conference that will be timely and relevant. Because all of us are connected with the pharmaceutical, biotech and/or medical device industries, we share a clear understanding of the compliance demands that are imposed on our industry in the current, hard-pressed business and scientific environment. We recognize how essential it is to be up to the minute in understanding the challenges that our membership experiences.

The PDMA Alliance, now in its 26th year, came into being in the aftermath of the Prescription Drug Marketing Act (PDMA), which brought a heightened level of regulatory oversight to a variety of industry marketing practices—specifically, sampling to physicians. In the intervening years, our annual Sharing Conference has brought education and operational guidance to these marketing practices, as well as the continually evolving new industry guidelines.

Over the past several months, the Alliance Board has been evaluating both existing and new compliance issues of concern to our members. Among the important topics that we will be revisiting are:

We also agreed that opportunities for expanded learning are plentiful in areas such as fulfillment and logistics, digital marketing, allocation analysis, sales force automation, customer relations, supply chain management, field technology, commercial operations, promotions, sales support, and operations.

The board shared their awareness of the concerns of worldwide consumers and businesses alike, particularly anxieties related to healthcare. The cost of healthcare and the economic impact of new and existing diseases and epidemics are among the issues that have led to uncertainty and frustration. The professionals who are addressing these fears, those directly or indirectly involved in cost management, drug discovery and development are under scrutiny, questioned and criticized in unprecedented ways. Good business practices related to pricing, reliability and ethics are being challenged. Doubts about the credibility of pharmaceutical, biotech and medical device companies are driving the potential for new legislation and more regulations, possibly more stringent than ever before. The impact on compliance  is obvious.

The overriding mission of every annual Sharing Conference prevails. We see the conference as an educational event—providing knowledge and information to people in various positions related to compliance, helping them to understand the impact that recent and anticipated legislation and regulations has on their daily responsibilities. We are committed to examining the laws and their ramifications through the sharing of attendees’ individual business experience—both successes and setbacks. And we support this sharing with the knowledgeable input of subject matter experts, as well as with the counsel of enforcement professionals. It’s clear there is no compromise when it comes to hearing from the wide range of sources who are specialists in their respective areas.

In planning the 2016 Sharing Conference, the board agreed that looking at compliance from the perspective of continual learning would be the focus of our conference theme. We decided to broaden the methodology and depth of the compliance learning experience. We built a conference program that would address new legislation and enforcement areas while continuing to deliver valuable insights into existing regulations that have been enforced for many years in the past.

We also knew that we must remain both relevant and valuable to the diverse group of individuals who comprise the Alliance. The very nature of their individual responsibilities leads to different interests; their corporate cultures and therapeutic focus areas often drive their learning preferences. We recognize that knowledge essential to compliance must consider regulations beyond the guidelines of the PDMA, Physician Payments Sunshine Act and the HHS Office of Inspector General. We reminded ourselves of the compliance learning continuum: how we must frequently return to many of the same subjects, uncovering deeper layers of understanding year after year. Because it is clear that learning is an ongoing endeavor, we summed it up briefly and succinctly. For professionals in the compliance world, Learning Never Stops.

2016 Sharing Conference attendees will experience more content than what they have encountered in previous years. Our agenda will feature two general sessions keynoted by representatives of government regulatory agencies, twenty-two workshop sessions presented by industry experts, and eight speed sessions. The latter are new learning events featuring 15-minute dives into subjects not covered elsewhere during the conference, but identified as important  to the current or future responsibilities of our audience.

Though we will be delivering more valuable content than ever before, our timeline has been condensed. The conference will be conducted over two and a half days beginning midday Monday, and will not be held over a weekend. This change in schedule was enacted in response to our attendees’ wishes, as a good number of last year’s attendees requested that we avoid beginning the conference on  a Sunday.

Every year, we work hard to identify and invite the experts who will bring insights to attendees that are not forthcoming from other sources. This year, we will again hear from the Centers for Medicare and Medicaid Services. We anticipate that they will give us further insights into Open Payments and the processes that are in place to support the program. We will also be hearing directly from members of the FDA, OIG and other government agencies.

Our speakers will elaborate on the implications of a wide range of compliance regulations. While some of these topics have previously been part of our agenda, they are being revisited with good reason: experience has shown that as soon as we have addressed the intricacies of a specific compliance issue, another aspect of the ramifications surfaces. It sometimes seems that the answer to every question drives us to yet another line of inquiry. And still more concerns develop over the course of each conference, which is one reason why our Sharing Forums—which are wide open, two-way dialogue on any compliance issue—are always among our most popular sessions.

Our annual 2016 Sharing Conference is recognized as the place where compliance professionals can get the answers they are looking for through sharing. The shared expertise of the experts; the shared innovations and solutions from our vendor partners; and significantly, the experiences that our pharma, biotech and medical device attendees share with each other. Without a doubt, these are the incomparable benefits that are exclusively offered by the Alliance year after year, soon to be our 26th year of sharing.

Conference registration is now open. Please go to 

Uncle Bob’s Self Storage Corporate Alliance

Deb Segura is the executive director of The PDMA Alliance Inc., the not-for-profit organization behind the 2016 Sharing Conference, now in its 26th year.

When it Comes to Compliance, Learning Never Stops

 Fig. 1. Over 200 CVD drugs are in development. Credit: PhRMA[/caption]

When looked at as a unified market, cardiovascular disease (CVD) is a very large, heavily populated ecosystem, inhabited by large numbers of healthcare delivery systems, therapeutic drugs, medical devices and drug/device combinations, patient support systems and advocacy groups. All this befits CVD’s continuing status as the No. 1 killer, ending the lives of 610,000 Americans each year (and 15 million worldwide, according to WHO). The American Heart Assn. estimates that 85 million Americans (roughly one in three adults) have at least one form of CVD.

Waves of new pharmaceutical products—antihypertensives, beta blockers, ACE inhibitors, statins, beta agonists, alpha blockers, alpha agonists, sodium channel blockers, calcium channel blockers, vasodilators, renin inhibitors, angiotensin receptor blockers, diuretics and thrombolytics—have been brought to market over past decades; most of these products are now generic. But that hasn’t dampened the enthusiasm of drug developers to go after new ones; some 200 CVD drugs are in clinical trials, according to PhRMA. However, many of the latest drugs are meeting stiffening resistance among prescribers, in large part due to high cost and uncertain medical benefit.

Another issue affecting cardiovascular care is that a worrisome number of CVD drugs are in short supply. Data from FDA and the Univ. of Utah Drug Information Service (a recognized authority on this subject) indicate that one out of 10 drugs on short-supply lists during the past decade or so have been for CVD. In many cases, the drugs are first-line therapies for which there are few alternatives. FDA has had some success in reacting to the shortages, but for a therapy class as broad as CVD, the situation  is worrisome.

In terms of the drug spend associated with CVD, the 2015 Express Scripts Drug Trend Report indicates that both cholesterol and high blood pressure (and related CVD disease management) remain among the top five costliest traditional drug therapy classes, and together accounted for 25% of the total traditional drug spend in 2015. However, thanks to the increasing availability and use of generics in both categories, the US drug spend on cholesterol-lowering drugs was down by 9.2% in 2015 (compared to the prior year), while the drug spend on blood pressure and other CVD medications was down by 12.5% in 2015. Today, generics account for 83% of all anti-cholesterol medications used currently.

Express Scripts projects further decreases in the drug spend for anti-cholesterol medications of 11–14% each year during 2016, 2017 and 2018, as the last popular branded statins Crestor (rosuvastatin) from AstraZeneca, Zetia (ezetimibe) and Vytorin (ezetimibe/simvastatin) from Merck all give way to generic competitors in 2016 and 2017.

Similarly, annual spending for blood pressure and other CVD medications are projected to decrease by 4–9%/year during 2016, 2017 and 2018, in part because generic alternatives to Benicar (olmesartan medoxomil) and Benicar HCT (combined with hydrochlorothiazide), the largest-selling angiotensin receptor blocker (ARB) will become available in October 2016.

Despite the fact that several eagerly anticipated new CVD-related medications have been approved over the past year or so, many have entered the ring with more of a whimper than a bang. These high-cost branded products face a steep acceptance curve, as they enter classes that are already dominated by proven generics. The same pressures impact the market for drug-device combinations and medical devices, as well.

As a disease state, CVD casts a long shadow, encompassing numerous chronic and deadly disorders related to the heart and blood vessels. These include congestive heart failure, angina, arrhythmia, hypertension, coronary artery diseases, peripheral artery disease (PAD; a marker of systemic atherosclerosis), thrombosis, ischemic heart disease and stroke. Many of these conditions are related to precursor health conditions, including high blood pressure, high cholesterol, diabetes and obesity. Underpinning it all are the many lifestyle factors—unhealthy diet, lack of exercise, obesity, tobacco and alcohol use among others—that are directly or indirectly to blame.

CVD medications typically work by either enhancing the heart’s pumping capacity, increasing oxygen supply to the heart, or reducing the levels of low-density lipoprotein (LDL) cholesterol (so called “bad” cholesterol) or raising high-density lipoprotein (HDL) cholesterol (so-called “good” cholesterol).

One of the newest medicines to treat heart failure, Entresto (sacubitril/valsartan) from Novartis, which is a combination of angiotensin receptor blocker (ARB) valsartan and the neprilysin inhibitor sacubitril. It was launched in 2015, and to the surprise of many industry observers, it has been met with some resistance. “Entresto is notable for both its clinical trial results—with significant mortality benefit demonstrated—and for the cautious reception it has received in the provider community,” says Michael Kleinrock, director of research development, IMS Institute for Healthcare Informatics. “Some observers expected wider usage based on Entresto’s clinical profile, but have had to readjust their expectations based on lower usage since it first launched.”

Novartis reported first quarter 2016 US sales of $17 million, which some industry observers consider to be a slow start for a presumptive blockbuster drug. Entresto encountered such a steep uphill climb right from the starting gate in part because “the medicines it would replace are already well understood by doctors and most are available generically,” says Kleinrock. And, because “patients with heart failure typically skew toward relatively lower socio-economic status, Entresto’s high cost will always be a factor.” He notes that many prescribers anticipate that these patient demographics and high drug costs, coupled with a high drug copay and the burden of requiring a prior authorization, will reduce adherence when Entresto is prescribed. “If doctors are not sold on the clinical concept enough to risk potential cost-based non-adherence, they might be reluctant to prescribe the drug,” he adds.

Another area of general interest within CVD is the new class called novel oral anticoagulants (NOACs), which reduce blood clots to prevent thrombosis or stroke. Examples include Pradaxa (dabigatran etexilate) from Boehringer Ingelheim, Xarelto (rivaroxaban) from Janssen, and Eliquis (apixaban) from Bristol-Myers Squibb. “These drugs are steadily gaining wider adoption, replacing decades-old generic warfarin blood thinners,” says Kleinrock.

“For manufacturers of newer, high-cost CVD medications, obtaining favorable coverage and formulary position is the first step to reducing barriers to patient access. This requires collaboration and communication with payers, who are becoming increasingly concerned with real-world value and the effect a drug will have on the overall patient experience,” says Mike Eaddy, PharmD, PhD, VP of real world evidence for Xcenda, a part of AmerisourceBergen. “In the absence of real-world data upon product launch, manufacturers must follow through to develop an evidence-based strategy that leverages real-world sources of information to fill evidentiary gaps,” he adds. “This includes electronic medical records, insurance and pharmacy claims data linked with lab data, and prospectively designed observational studies to demonstrate that these products are working and providing effective clinical outcomes.”

“Medicines that treat cardiovascular-related illnesses represent an incredible new opportunity for patients, caregivers and prescribers, and long-term opportunity for payers, in terms of promoting greater health and wellness and offsetting major cardiovascular events down the line,” says Derek Cothran, VP and lead, strategic account management, Lash Group, a part of AmerisourceBergen.

However, CVD drugs now have to navigate more complex treatment protocols, due in part to their rising costs. For instance, Cothran explains, “Payers have placed strict utilization restrictions on up to 80% of initial prescriptions for some of today’s CVD medications, such as the classes for deep vein thrombosis (DVT), venous thromboembolism (VTE), congestive heart failure or the PCSK9 inhibitors (discussed below), with many of these taking more than 10 days for a determination.” Against this backdrop, many manufacturer-sponsored programs “have planned for this and recalibrated their plan offering, often providing ‘starter’ or ‘bridge’ products to patients who are in need of medicine and are unable to wait for a payer decision.”

 Fig. 2. CVD fatality is on a downward slope.[/caption]

PCSK9 inhibitors receive a lukewarm welcome

Nowhere is this playing out more fiercely in CVD right now than within so-called PCSK9 inhibitors—the newest class of cholesterol-reducing medications that are approved for a relatively narrow subset of patients (those with severe hyperlipidemia) who are at high risk for cardiovascular disease and aren’t able to control LDL cholesterol through diet or the highest-tolerated dose of statins. Unlike the widely used pill-form statins, most of which are now in generic form, the PCSK9 inhibitors are costly, self-injectable biologic agents, which must be self-administered every two weeks or once/month, so while they have certainly been generating a lot of interest, adoption has been slow to materialize.

In mid-2015, the first of two PCSK9 inhibitors medications were approved— Repatha (evolocumab) from Amgen and Praluent (alirocumab injection) from Sanofi/Regeneron. Pfizer also has a PCSK9 inhibitor candidate (bococizumab), which is currently in Phase III clinical trials. Right from the start, these introductions were met with mixed emotion among key stakeholders. While clinical trial data for both have confirmed impressive results, each has a list price around $14,000 per year, so it takes a strong case to justify the use of PCSK9 inhibitors in the face of proven, low-cost, generic oral statins.

“The manufacturers and insurers alike have been somewhat surprised. While these drugs have been making significant gains in terms of clinical effectiveness, they have not been greeted very warmly, not just because of their high price tag, but also because the existing standards of care have so much long-term, real-word CVD event outcomes data to really validate the benefit-risk profile of the existing products,” says John Doyle, DrPH, MPH, SVP, advisory services for Quintiles. “As a stakeholder you say ‘Okay, this looks promising, but only when long-term real-world evidence becomes available for the newer agents can a true apples-to-apples comparison occur,’ and with a higher price differential, payers are saying ‘Let’s just pull back the reins a bit.’”

Last September, just as the PCSK9s entered the market, the Institute for Clinical and Economic Review, a nonprofit policy group, issued an analysis claiming that Repatha and Praluent should be priced closer to $2,200 per year based on their value relative to generics. Both Amgen and Sanofi/Regeneron are in the process of gathering real-world evidence to verify that the favorable clinical trial results can be sustained under messy real-world conditions, but the earliest of these results are not expected until 2017. Despite ICER’s assertions, both Amgen and Sanofi/Regeneron have stood by their pricing policy, citing the significant unmet need for patients who would be best served by these medications and the long-term clinical outcomes and savings potential they promise.

“The expectation is that once the real-world data confirms—or raises questions—about the clinical trial results, payers and providers will be able to adapt their understanding of appropriate use,” says Kleinrock of IMS Institute. “Are they worth the cost multiplier for more patients? Only time  will tell.”

Nor should it be overlooked that while the PCSK9-generic comparative effectiveness is being evaluated, the manufacturers “will also have to figure out how they can differentiate themselves from one another,” adds Doyle of Quintiles.

PBM Cigna isn’t waiting for eventual real-world data. In May, the company announced that it had finalized “value contracts” with both Amgen and Sanofi/Regeneron, to tie the negotiated price of these two new PCSK9 inhibitors directly to improved patient health. Specifically, if the drugs meet or exceed expected LDL-C reduction across Cigna’s broad patient base, the negotiated price remains in place; if the patients are not able to reduce LDL cholesterol levels as expected, the two drugmakers will further discount the cost of the drugs, explains Christopher Bradbury, SVP, Integrated Clinical and Specialty Drug Solutions for Cigna Pharmacy Management. “Innovating through the contracting approach is one way we are helping our customers and clients to receive more value for their healthcare dollar, and this is important for the high-cost PCSK9 inhibitors because as prescribing grows within this class, they could impact significant numbers of patients.”

The agreements put manufacturers’ own dollars at risk,” he says, which will “introduce a new form of competition” in the market. The company is the first to strike independent, value-based agreements with both sets of manufacturers. Cigna has already had success using similar value-based contracts with pharmaceutical companies covering other high-cost medications for cholesterol, heart failure, diabetes, multiple sclerosis and hepatitis C.

Meanwhile, Express Scripts’ Cholesterol Care Value Program (CCV) “combines discounts on these PCSK9 therapies with rigorous clinical documentation and utilization-management strategies and a total cost cap for participating plans, to minimize unnecessary risks and wasteful spending, and help hold down payer’s drug spend on these medications.” With its conscientious effort, Express Scripts says its National Preferred Formulary clients collectively will spend “approximately $750 million on PCSK9 inhibitors in 2016—far lower than industry forecasts.”

In addition to the world of oral and injectable therapies that are available to treat CVD and its underlying conditions, a host of medical devices are also available or under development to further improve interventional cardiology and endovascular care. These include:

Diagnostic devices—such as wearable and insertable heart-monitoring devices

Structural-replacement elements—such as transcatheter mitral valve replacement (TMVR), transcatheter aortic valve replacement (TAVR) devices and transcatheter pulmonary valve replacement (TPV) devices

Interventional devices—such as pacemakers, automated external and implanted defibrillators, stents and bioabsorbable stents and more.

Taking the concept even further, a growing number of novel drug-device combinations are also available or under development, to facilitate drug delivery. These include drug-eluting stents or balloons, drug-eluting vascular grafts, and more. “We are beginning to see a blurring of these two entities in the world of cardiovascular care,” says Pamela Froneberger, RN, BSN, Director, Healthcare Solutions for FTI Consulting (Charlotte, NC). “Pure medical devices such as pacemakers and drug-device combinations like drug-eluting stents now play different, yet synergistic roles within the care and treatment of cardiovascular disease.”

In April, a leadless, single-chambered pacemaker from Medtronic, the Micra Transcatheter Pacing System, received US approval. “The device, which will be marketed for specific atrial fibrillation patients, works similarly to other pacemakers—except that it is a self-contained device that is implanted directly into the right atrium of the heart and has no leads,” says Froneberger. “Market-adoption rates for this product will be something to watch.”

Froneberger highlights transcatheter aortic heart valve replacement as a good example of where device-based CVD care is going. [1] The valve is implanted via minimally invasive surgery—including simply passing it up an artery into the heart; and without removing the patient’s own heart valve—thus avoiding open-heart surgery and the complications that entails. Nevertheless, she says, TAVR requires a complex, multi-disciplined approach to care involving a complex team of interventional cardiologists, anesthesiologists, echo cardiographers, radiology/imaging and cardiothoracic surgeons, all of whom must effectively communicate and collaborate with each other to ensure patient success. “Most hospitals that have TAVR programs are struggling with the peer cross-collaboration piece more than the technical piece,” she adds. “They are also struggling to show positive rates of return on their program investments—especially if they are not monitoring and measuring cost per procedure/physician on a regular basis.”

Edwards Lifesciences (Irvine, CA) and Medtronic are two of the suppliers of  the therapy.

Not surprisingly, the supply chain for medical devices and drug-device combinations used in CVD is complex. “In today’s competitive healthcare environment, the economic question for manufacturers of drug-device combination products has to be: ‘Is there a quantifiable economic value for patients to use these products above and beyond what has historically been used to treat a particular disease?’” says Froneberger of FTI Consulting. “To the hospital that purchases these products, the question becomes: ‘If we buy this drug-device combination product instead of the earlier non-drug model, how much more are we going to pay? And, will we get our money back or lose our shirt?”

“Unless there are credible, peer-reviewed articles on the drug-combo products—that are not sponsored or funded by the manufacturer—medical devices, both drug-combo or not, are bumping up against market-entry barriers like never before, making mass market adoption rates more difficult,” says Froneberger, adding: “If manufacturers aren’t answering these questions themselves months or years before the product moves from the conceptual drawing board to the hospital’s loading dock, they are likely to see their product traverse a journey to nowhere land.”

A wave of recent mergers in the CVD medical device space signals the partners’ intentions to exploit the natural synergies that exist between CVD drugs, medical devices and drug-device combination products, and industry observers say that such consolidation gives merged entities better bargaining power with hospitals.

 In April 2016, Abbott agreed to purchase heart-device manufacturer St. Jude Medical for $25 billion. According to the companies, St. Jude Medical’s strong positions in heart failure devices, atrial fibrillation and cardiac rhythm management complement Abbott's leading positions in coronary intervention and transcatheter mitral repair.

 In March 2016, Johnson & Johnson announced that pending regulatory approval, it is acquiring NeuWave Medical, a privately held medical device manufacturer.

Medtronic plc recently made two strategic acquisitions in the medical devices field: In August 2015, it acquired Twelve, a Redwood City, CA-based developer of a still-in-development transcatheter mitral valve replacement device, for $458 million, and in July 2015, Medtronic acquired Carlsbad, CA-based medical device maker RF Surgical Systems for $235 million.

Because the risk factors for heart disease and stroke are so directly impacted by lifestyle choices, patient-support initiatives play a critical role in reducing the long-term risks (and costs) of CVD through the proper management of threat factors such as diet and exercise, obesity, high cholesterol levels, tobacco and alcohol use, and sustained adherence to medications (especially those required indefinitely to manage chronic conditions). When it comes to costly biologics and other specialty medications, comprehensive patient-support programs are often administered through a centralized, branded hub, which combine a mix of high-tech and high-touch program elements to educate patients and providers, remove financial and clinical barriers to access, and support long-term adherence.

For instance, hub programs often help patients to verify insurance reimbursement and remove financial barriers by connecting them with branded coupons and copay-offset coupons that can reduce out-of-pocket costs for medications, or helping them to enroll in patient assistance programs for which they may be eligible, to access the drug at no cost.

“With access and reimbursement being such a huge hurdle for so many patients, brand teams must remember that the copay card is really just the starting point for engagement with patients—the real work starts in terms of how you continue to engage them beyond Month 1, 2 or 3,” says Javier Castillo, executive director of Program Strategy and Design for the Health Management Solutions (HMS) group of Quintiles.

“Clinical nurse-educators, providing individual training or interacting with patients and caregivers through virtual webinars and group settings, provide a particularly effective way to educate enrolled patients, helping them to understand their disease and their medications and to stay on therapy, even if the condition is asymptomatic, as is so often the case in CVD,” he adds.

Targeting physicians with support tools is equally important. With today’s newer, high-cost CVD medications, “physicians often encounter complex payer requirements for patient medical histories, prior authorizations and more, which can create a significant administrative hurdle and administrative restrictions that must be overcome before a patient can start therapy,” says Kleinrock of IMS Institute.

“Branded hubs continue to provide an effective way to give patients and prescribers access to a number of tools to manage the many utilization restrictions that are imposed by payers to control costs and reduce inappropriate prescribing,” adds Cothran of Lash Group. “Program elements may include easy phone access to trained specialists who can coach prescribers and their staffs through the complex prior authorization (PA) and step therapy protocols and related documentation, and the ability to leverage electronic PA tools that can streamline the process.”

“Throughout CVD, there’s quite a need for education up front and the practice often needs tools to support the patient,” says Castillo of Quintiles. “It’s really important to develop programs that target the doctor, nurse, family nurse practitioner and physician assistant, so they are aware that the product’s support programs go way beyond just the copay-assistance card. You get a much higher level of enrolled and engaged patients when it’s the healthcare professional who is recommending enrollment in the program. At the end of the day, hub programs are only as good as the volume of patients that are being driven through them.”

A big part of patient support is changing lifestyle habits in conjunction with the drug or surgical interventions. “Specifically for CVD patients, many patients have a history of poor eating and exercise habits, do not seek routine healthcare and are not very good about taking their medications,” says Amanda Dean, PMP, account manager with Triplefin. “When a patient is prescribed a medication (for instance, an oral anti-platelet agent following a CVD event), it’s really critical to develop programs and support tools that help the patient understand that they must now manage a chronic condition—not just that they had a heart attack and the doctor has fixed it.”

“Patients who have had a heart attack have scared themselves and they’ve scared their families, so the contact center professionals try to capitalize on this during coaching sessions, by, for instance, helping patients truly understand what their chronic medication is able to do for them,” she adds.

“Because of their clinical experience and patient focus, nurses are not only able to provide standardized, program-specific information but they can also pick up on subtle cues, probe further and assess the patient, personalizing an approach based on individual needs,” adds Castillo of Quintiles.

Traditionally, high-tech and high-touch patient-support programs that have been the domain of drug manufacturers (and their third-party partners) offering high-cost, high-complexity specialty medications. However, an interesting conundrum emerges within cardiovascular disease—because the need for constant hand-holding is high, yet the majority of the drugs that are used today to treat high cholesterol and high blood pressure are now generic.

In light of this disconnect, many PBMs, including both Cigna and Express Scripts, and disease-specific groups such as the American Heart Assn., some advanced healthcare systems and others, have stepped into the breach, offering a variety of online programs, and clinical, and health and behavioral coaching support, to promote wellness and medication adherence for patients.

“Patient support programs definitely tend to dwindle to just copay support for many generics, since there is no real profit margin available—these types of robust support programs still fall to the branded manufacturers,” says Castillo of Quintiles. “In fact, for brands that are approaching patent expiry, these valuable adherence-related programs can help to differentiate the branded drug against the generic in the eyes of physicians, and may help to preserve some market share once the generics enter the market.”

“We take a comprehensive approach to supporting patients with cardiovascular conditions, whether they are using a generic or specialty drug, as our focus is on improving overall health and total healthcare costs,” adds Bradbury of Cigna. “For instance, we work directly with our customers through many channels, engaging not only patients but physicians. We help customers understand the risk factors of non-adherence, develop healthier behaviors and provide insight so that physicians can help to address those blind spots.”

Drug shortages have been a pervasive and persistent problem impacting the US healthcare landscape in recent years. The number of active shortages of “medically necessary drugs” in the US has increased more than sevenfold since 2007, and such shortages can last for months or even years. A significant number of the drugs impacted by shortages include those used to treat cardiovascular patients.

“Shortages of cardiovascular drugs have become increasingly common, representing an ongoing public health crisis,” stated Brent Reed, PharmD, of the University of Maryland School of Pharmacy, in a recent American Heart Journal article. [2] “They have become a familiar aspect of contemporary clinical practice, especially in acute and critical-care settings, where complex clinical decisionmaking can be further compounded by limited access to common standards of care.”

Drug shortages can lead to delays or denial of treatment for patients, medication rationing (which raises obvious ethical concerns), and substitution of alternatives therapies that are often not identical. “When evidence-based alternatives do not exist, clinicians are forced to second- or third-line therapies, which may be less effective or confer a greater risk of adverse events or dosing errors,” says Erin Fox, PharmD, FASHP, director of the University of Utah Drug Information Service (UUDIS). She notes that medication errors are much more likely to occur when a different drug, dosage, strength or formulation, or drugs with different labels or different administration routes, must be substituted. “With so many patients impacted by CVD, ongoing shortages create major medical implications,” she adds.

According to FDA, 65% of all drug shortages are caused by manufacturing and quality issues and failure to comply with current Good Manufacturing Practices (cGMP). “The economics are definitely on the side of the branded products and they have the money to build in some redundancy and they have a vested interest in not engendering bad press,” says Fox. “FDA should implement a metric—with real financial incentives and penalties—that would incentivize and reward companies to strive for the highest quality standards to enhance the reliability of their suppliers. Right now, it’s pass/fail on quality—you’re either on the market or you’re not.”

After excluding electrolytes and intravenous fluids, UUDIS data indicates that one out of every 10 shortages from Jan. 1, 2001 to Sept. 30, 2014 involved drugs used in the management of CVD. Of the 181 shortages involving cardiovascular drugs, the majority (68%) represented therapies used in the routine management of CVD (such as vasodilators and other antihypertensives, antiarrhythmics and diuretics). Another 19% represented drugs related to coagulation, thrombosis, or flood formation (such as heparin), and 13% represented vasoactive drugs (such as dopamine, norepinephrine), which are required in critically ill patients, says Fox of UUDIS, who co-authored the American Heart Journal article. The situation is especially troubling within the realm of CVD, she says, because so many of the drugs in question are very clear first-line therapies—such as nitroglycerin, heparin, epinephrine and others—and have few, if any evidence-based alternatives.

Critical shortages of intravenous (IV) nitroglycerin began to emerge in early 2014, impacting thousands of patients each year. “Nitroglycerin is pretty much what any patient who has a heart attack and goes to the ER is going to get,” says Fox. As part of the workaround solution devised by FDA, Arbor Pharmaceuticals began importing from Germany a formulation of nitroglycerin marketed as glyceryl trinitrate (Nitronal). “Use of this alternative raises the risk of dosing errors, due to the use of a different concentration of this drug compared to the traditional US product,” says Fox.

In a similar vein, according to FDA [3], a 2010 survey of pharmacy directors showed that the annualized personnel costs associated with managing drug shortages across US hospitals is estimated at $216 million/year, in terms of time spent by physicians, pharmacists and nurses on tasks such as investigating alternative agents, developing action plans, managing inventory, adjusting computer systems to use alternative agents and educating staff. Fox of UUDIS notes that this estimate is conservative, as it relates only to costs incurred by hospitals but not all venues impacted by drug shortages (such as ambulatory infusion centers, community pharmacies and long-term care facilities), and the number of persistent drug shortages is higher now than it was during the survey period.

Part of the FDA Safety and Innovation Act (FDASIA) of 2012 expanded FDA’s regulatory authority and specifically requires manufacturers to notify the agency at least six months in advance (or as soon as practicable) of any interruptions or discontinuations in the production of critical drugs. FDASIA empowers FDA to use tools such as expedited reviews of new applications for generic drugs, increased regulatory discretion, and other market and manufacturing interventions to identify alternate manufacturers who might be able to ramp up production to reduce the magnitude or duration of  the shortage.

Since the enactment of FDASIA, early warning notifications from manufacturers to FDA have increased six-fold, and “the lead time gives FDA at least a fighting chance to step in and see if it can get other manufacturers to step up to address the pending shortage,” says Fox. And this has yielded some impressive results: FDA was able to circumvent 282 drug shortages in 2012, 170 drug shortages in 2013, 101 drug shortages in 2014, and 128 drug shortages in the first three quarters of 2015, according to the 2015 annual report to Congress [4].

Froneberger, Pamela, FTI Clinical Passport—2015 Product Trends in Cardiovascular and Endovascular Care, FTI Consulting White Paper, March 2015, Accessed at: 

http://www.fticonsulting.com/insights/articles/2015-product-trends-in-cardiovascular-and-endovascular-care

Reed, Brent N., Fox, Erin R., et al, The Impact of Drug Shortages on Patients with Cardiovascular Disease: Cause, Consequences and a Call to Action, American Heart Journal, May 2016, Vol. 175, pp. 130–141; http://dx.doi.org/10.1016/j.ahj.2016.02.004

U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Approach to Addressing Drug Shortage; Public Workshop, 

http://www.fda.gov/drugs/newsevents/ucm265968.htm

Dept. of Health and Human Services and FDA, Third Annual Report on Drug Shortages for Calendar Year 2015. 

http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM488353.pdf

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