By Suzanne Shelley, Contributing Editor

Non-adherence to therapy is widely recognized as an ever-present problem in healthcare generally and the pharma industry specifically, which forgoes some $250 billion annually in lost sales. The picture is changing, somewhat, from past years, as health systems now have incentives (through Medicare’s Star program of financial incentives and penalties for health outcomes) to improve patient adherence. In the specialty pharmaceutical arena, manufacturers now have substantial incentives to improve adherence and outcomes, through the expansion of value- or outcomes-based contracting.

Leveraging data from off-label prescribing

Patient-support and hub service providers assist their manufacturer clients in running adherence programs, and manufacturers are reaching out to the specialty pharmacies that they work with for assistance as well. For the most expensive specialty products, it’s not hard to justify the expense and effort of “high touch” personal interactions with patients, via care coordinators or pharmacy technicians. The trend now, though, is to use technology to automate some or all of adherence programs, thereby getting better results at lower overall cost.

There are two aspects to the technology trend: developing better analytics to predict patient behaviors during therapy; and establishing a line of communication through the latest digital technologies, notably smartphone apps, to reach patients “where they are at” in their day, or in their patient journey.

“Historically we’ve been very hypothesis-driven around adherence — we create a hypothesis and then a solution and then we measure whether the solution worked,” says John Doyle, SVP@IQVIA. However, with advances in the breadth and depth of real-world data and real-world experience available today and advanced modeling and machine-learning analytic techniques, stakeholders “don’t necessarily need to start with a hypothesis. We can now look for patterns and then use inductive reasoning and run models to test the impact of newly identified trends.” For instance, he notes that the search for factors impacting adherence should integrate not just the usual healthcare data sources, such as payer and pharmacy databases, EHR and patient registry data, but financial data sources as well (such as de-identified credit scores). “This can shed light on how socio-economic challenges may further impact adherence trends, thereby allowing more-tailored interventions to be created.”

Adheris Health LLC, a Syneos Health Company, partners with large branded phama companies to deliver targeted adherence-support information and motivational messaging directly to patients and physicians, via the EHR system (at the point of care) and the retail pharmacy (at the point when prescriptions are picked up). Using proprietary analytical methodologies to gain insight into patients’ behaviors, needs, and emotions, the messaging and outreach can be tailored as needed, allowing for improved clinical outcomes and brand performance.

“Today we have insight into more than half of all retail prescriptions written,” says Michael Occhipinti, VP, Analytics. “Working with our EHR vendor partners and retail pharmacy partners, we have direct access to 295,000 prescribers, 197 million patients, 2.25 billion prescriptions per year dispensed from 26,500 pharmacies, so we are able to support the patient through the most critical moments of care to ensure they stay on their prescribed therapy to maximize both brand and patient performance.” He notes that the company routinely use several years’ worth of patient longitudinal data to help decide where and when to intervene with the most appropriate outreach (in terms of messaging and timing) for the biggest impact.

Adheris Health also uses data analytics (and randomized test controls) to assess the effectiveness of any brand-specific outreach efforts, so the adherence-related behaviors of patients exposed to the campaign can be assessed, and the program finetuned going forward, he adds. Using logic that is incorporated into the pharmacy workflow, the company also generates the familiar, targeted drug- and disease-specific messaging printed in the information packet that is stapled to the prescription bag, with messaging that may be related to not only the prescription being picked up, but to other diseases the patient may be managing, as well.

Upwell Health, a company that works primarily with pharmacies and insurers to support patients, makes use of direct shipment, telemedicine and educational support tools, according to Alison Wistner, CEO. Upwell also provides a variety of high-touch, wraparound services, helping patients work with pharmacies and insurance companies to ensure access to all of their medications at the lowest possible OOP costs, and curates and shares informative content, including news, videos, reports and research, through its website, to help patients remain informed and engaged.

The adherence challenge becomes more acute when the condition is asymptomatic and patients “feel fine” without their medications — until an episode occurs — despite the known threat that poor adherence poses to their long-time prognosis and overall health outcomes. “Each solution being explored today has its own strengths and weaknesses, but it’s important that patients arrive at a point where they view taking prescribed medications as an important part of their overall health — rather than a burden,” says Sub Datta, CEO of CompanionMx, a spinoff launched in late 2018 from voice-analysis company Cogito. “If patients are engaged through a more holistic program, they feel empowered as an active and critical part of the process. Then we can meet them where they are through digital applications, clinician dashboards or other interventions.”

CompanionMx’s Companion smartphone app uses voice-analysis technology with weekly check-ins with patients; patented algorithms analyze the voice recording to assess patient status, which can then be shared with a care team. In a preliminary six-month study of more than 100 patients with diagnosed mood disorders, CompanionMx found that 86% of survey responses were taking their medications as prescribed — “a rate that is significantly higher than typical medication adherence statistics for mental health, which is a reflection of increased patient engagement through the platform,” says Datta.

Groove Health offers an interactive mobile app that combines existing healthcare data, patient-generated input and predictive analytics to provide more personalized engagement. The company’s mobile app not only streamlines medication management (with automatic reminders, alerts to potential drug-drug interactions and more), but features an AI-powered chatbot, dubbed Maxwell. “As Maxwell interacts with the patient, it learns more about the patient’s particular barriers to adherence and can respond with tailored content, in order to spur behavior change among patients,” says Andrew Hourani, CEO and Co-Founder of Groove Health. Besides the information forwarded to the patient, the chatbot collects voice data “provides a unique view into the types of barriers the patient may be facing and build a more-detailed profile of that patient so that someone on their care team can take provide tailored support.”

“Human interaction and empathy are the hardest to replicate — you will never really be able to fully replicate a trained medical professional interacting directly with a person,” says Hourani. “But maintaining dedicated staffing is costly, and even if a pharmacist or coach talks to a patient once or twice when the patient is initiating treatment, there will be long stretches of time that the patient has no interaction with that specialist.” For a typical patient living with Type 2 diabetes, “you can count the time spent with a doctor in terms of a few hours in any given year — yet the need to properly manage medications and side effects and symptoms of disease progression is happening every single day,” he adds. “The Maxwell chatbot offers a great complement to that, by collecting and delivering the best information to answer any question that arises for the patient.”

The initial commercial-scale versions of the Groove Health platform have had a disease-specific focus (targeting patients with cardiovascular disease (CVD), diabetes, high blood pressure or high cholesterol) developed in conjunction with several hospital and payer systems, with the specific goal to reduce readmission rates through improved adherence. These drug-agnostic platforms help patients to overcome adherence challenges, no matter what medications have been prescribed. The company is also in the process of developing partnerships with several pharma companies and hub providers to configure its adherence-improvement app.

HealthPrize Technologies has put its money on another behavioral strategy — gamification, an interactive offering that combines education, encouragement and rewards with proven gaming techniques — to improve medication adherence. Gamification-based efforts aim to counteract what behavioral economists call “present bias” — that is, one’s preference for immediate short-term rewards over longer-term (but more nebulous) gains. This is particularly important when it comes to asymptomatic conditions that require a lifelong commitment to therapy yet the perceived long-term gains (say, staving off a heart attack or stroke, or reduce the risk of progressive limb loss or blindness) may seem abstract today. “Because there is little in the way of instant gratification in the lonely, burdensome process of daily medication, apps that are based on gamification aim to provide fast, fun and engaging feedback to overcome present bias,” says Tom Kottler, CEO.

Importantly, gamification has been proven effective with people across all age, gender and education-level demographics, and have been proven across many disease states, drug types and drug-administration routes. “We address medication adherence by addressing the psychological barriers many patients have, and we support habit change by rewarding patients for engaging in healthy activities, such as verifying prescriptions, reporting compliance and engaging with positive educational experiences like quizzes, surveys and videos,” says Kottler.

HealthPrize claims over one million patient users, and half of the top 20 pharma companies as clients.

Diabetes has proven to be a dynamic therapy area for raising patient adherence. In mid-2017, Roche acquired mySugr GmbH, the creator of a gamification-based mobile app to help patients with diabetes. The mySugr platform already had a million users in 52 countries at the time. Through this partnership, the app is now integrated with Roche’s existing Accu-Chek brand of blood glucose meters and test strips) and other forms of patient support (such as access to advice from certified diabetes coaches). Roche is now collaborating with Novo Nordisk, the world’s largest insulin provider, to integrate dosage information from Novo’s “connected pen” dispenser with Roche’s digital therapy-management platform.

Novo Nordisk also made headlines in 2017 when it partnered with Glooko, a diabetes data-management platform, and IBM Watson Health, to further expand its existing digital health offerings, enabling patients with diabetes to use their smart phones to sync their blood glucose measurements and self-reported activities, and integrates the data with up-to-date clinical content and resources and the company’s personalized support program.

HealthPrize is notable among adherence-technology providers for forging relationships with other parts of the drug-delivery ecosystem, specifically West Pharmaceutical, which manufactures syringe components and full-fledged prefilled syringe systems, WestRock, a compliance-packaging vendor, and Noble, which develops patient-training and education tools.

“Patients who are able to get hands-on practice with auto-injection and inhalation devices not only gain experience and muscle memory, but increase confidence while reducing anxiety about administering their medications at home,” says Joe Reynolds, research manager for Noble. Noble’s Smart Injection Practice Pad is an error-correcting trainer that uses proprietary electronics, smart sensors, audio, LED and tactile simulation to make patients aware of their errors in real time.

In a recent longitudinal study, Noble studied three patient cohorts that received different training stimuli during the14-day “decay” period following initial treatment in the doctor’s office. Among the group that had received no training (only written instructions), 56% made mistakes on critical steps during self-injection. By contrast, those who received basic training (using a resettable autoinjector training device and injection pad plus written materials) with or without an interactive training video, the combination of practice and mental preparation resulted in 100% successful completion of critical steps.

“We’ve put a lot of thought into how we design our training devices, in terms of human factors engineering, how people learn, how they forget and more, so our devices can most closely mimic the patient’s experience at home,” says Reynolds. Today, Noble has more than 30 different training devices on the market (each married to a specific branded therapy), and works closely with many major device manufacturers (including BD Safety Systems and SHL), to develop training devices and materials to ensure proper injection of medications for chronic, acute or episodic (emergency) therapies.

Articles

The longstanding adherence problem is yielding to new technology

Improving medication adherence with technology

Efforts to develop innovative, lifesaving medicines are always fraught with peril, and the clinical and commercial success of any investigational therapy is never guaranteed. Today, all stakeholders in the healthcare spectrum — pharmaceutical developers, payers, regulators, physicians and patients — are putting their money on the collection and analysis of many different types of real-world evidence (RWE) as a key enabling strategy, to close critical gaps in knowledge, give physicians and patients broader access to therapies, and help payers realize the actual value of those therapies in improving health and reducing costs.

Traditional clinical trials — while still the gold standard for establishing a drug’s risk/benefit profile and appropriate dosing strategy — are not able to fully elucidate how the drug, once launched, will perform under messy, real-world conditions, where patient populations are decidedly more heterogeneous than those studied in the trial. To better assess the full clinical profile and economic impact of high-cost specialty medicines over time, efforts are underway to explore and exploit various forms of real-world data that can be collected during patient care. Then, analytic, modeling and simulation tools, including artificial intelligence (AI) and machine-learning methodologies, can derive meaningful insights from those data.

But the process of using RWE is far from straightforward. Since all data are not created equal, a variety of industry stakeholders are developing standardization frameworks in an effort to establish some form of accountability and reliability, and thus foster greater confidence as RWE is being used to advance a variety of pharma and healthcare objectives.

Today, many data sources — some traditional, others emerging — are being used to improve insight during drug development. These include:

Pharmacy and specialty pharmacy dispensing data

Patient registries related to specific diseases and products

Patient-generated data (for instance, from in-home, mobile and wearable devices and sensors)

Behavioral data and insights collected from social media

Third-party aggregators of data records provide another good source of RWE. For example, IQVIA owns a comprehensive, global data portfolio representing more than 530 million de-identified patient records across 10+ markets, with more than 3,000 ready-to-use sources from EHR, hospital, pharmacy and claims data, as well as data related to genomics, mobile-health and patient-reported outcomes.

Similarly, the healthcare AI company Prognos claims to be the largest aggregator of laboratory data related to diagnostic testing in healthcare. Its database, called The Prognos Registry, contains more than 13 billion de-identified, HIPAA-compliant clinical records, representing more than 180 million patients, from more than 140 commercial diagnostic clinical-testing laboratories, according to the company. This enormous cache — which continues to grow over time — spans many different pathologies, in 50 disease states.

Today, a variety of advanced modeling, simulation and artificial intelligence capabilities are being used to analyze data from actual clinical practice to overcome the limitations of narrow or insufficient clinical trial data. Such efforts, according to Camie Britton, Senior Director, Real-world Data Services, Parexel International, include:

Mining unstructured data (for instance, from EHR clinical notes and sensors) for research purposes

Creating retrospective cohorts of patients to better understand how a drug works in a defined indication

Developing and validating algorithms based on EHR clinical notes or claims

Using such algorithms to distinguish and characterize targeted subpopulations as a means of supporting future research

“Two general approaches are emerging in terms of how drug developers are using RWE — greater use of classical, hypothesis-driven research, and the use of newer data-analytic tools including AI and machine-learning techniques that provide insight based on pattern recognition within vast data sets,” says John Doyle, SVP & GM, Real-world & Analytic Services, IQVIA, and faculty member, Department of Epidemiology, Mailman School of Public Health, Columbia University. “We should be looking at a hybrid approach, but we also need to challenge and ‘stress test’ the pattern-recognition results and inferences that are being made about causation, to ensure that they are based on sound scientific principles.”

The second annual RWE Benchmarking Survey, [1] from Deloitte’s ConvergeHealth unit, finds that 90% of global pharma companies either have or are building RWE analytical capabilities, and that applications range across the entire product lifecycle for these undertakings.

Once a drug has been approved and enters the marketplace, it is often prescribed to additional patient subgroups (beyond just the narrow patient cohorts enrolled in the clinical trial, or are specified in the approved label indication). The ability to study the drug’s performance in patients using the drug off-label is important, as it will reflect how the drug actually performs among a decidedly more heterogeneous patient population, and thus can help to paint a broader picture of the drug’s full clinical potential.

In some cases, RWE findings from such patients can help the drug maker to seek and gain regulatory approval for additional label indications for that therapy, and can help to inform clinical guidelines and other decision-support tools for use in routine clinical practice.

However, unlike the tightly screened patient populations enrolled in a formal clinical trial, patients seeking treatment for any condition under real-world conditions often have one or more comorbidities, and are already taking other medications that could lead to drug-drug interactions (DDIs). Those DDIs, coupled with unpleasant side effects or adverse events, affordability issues and other patient behaviors, often conspire to reduce the patient’s adherence to therapy, and poor adherence to therapy is one of the leading factors to undermine the clinical effectiveness and health outcomes that were demonstrated in the trial.

For many specialty drugs that are aimed at diseases with critical unmet medical need — particularly in oncology and rare or orphan diseases — fast-track or conditional regulatory approval provides an accelerated pathway for regulatory approval. “Giving patients faster access to these drugs is fantastic, but fast-track approval leaves an unfinished story still to be told,” says Doyle of IQVIA. “RWE becomes the only option to round out that conditional approval, to demonstrate safety, effectiveness and tolerability, across more diverse populations in real-world clinical settings over longer time horizons.”

Patient or product registries can yield data from a sufficient number of patients to enable statistically relevant subgroup analyses, and these findings can be used to seek expanded label indications and help demonstrate the therapy’s full value proposition to payers and Health Technology Assessment (HTA) organizations. “Such examples are exciting and they are really happening today, but frankly these RWE techniques are still being grossly underutilized to validate, extend and complement the findings of these clinical trials,” he adds.

Meanwhile, Zhen Su, MD, Chief Medical Officer for North America at EMD Serono cautions: “Monitoring how the drug responds in specific sub-populations in actual clinical settings can certainly help to elucidate who responds better to treatment, enabling drug developers to negotiate for label expansion for the drug. But drug developers must also be prepared for the fact that such efforts may also reveal patients who do not end up responding well over time, and this can lead FDA to shrink the label indication for that therapy.” This happened in June, when FDA announced it was restricting the use of Merck & Co.’s Keytruda (pembrolizumab) and Roche’s Tecentriq (atezolizumab) in first-line bladder cancer to patients who express high levels of PD-L1, revising the labels for both drugs to include a requirement for testing for PD-L1 expression. Treatment continuation can then be considered for patients responding to the drugs who are not eligible for cisplatin-containing chemotherapy, according to FDA. [2]

While RWE has historically been used to monitor post-launch safety and adverse events, drug developers are increasingly incorporating RWE-driven insights further upstream to improve clinical trial design and execution. For instance, RWE can be used to assess and validate specific biomarker hypotheses, or to create a “synthetic” control arm based on RWE derived from historic or contemporaneous patients being treated in actual practice and then use that synthetic arm in lieu of an actual control arm during the clinical trial.

“The need for clinical trials to run a control arm often creates redundancy and added time and cost for the drug developer, and for some diseases and drugs, it’s unethical to put patients into a control arm of a trial,” says Su of EMD Serono. “By comparison, the ability to create a synthetic control arm based on RWE can reduce drug-development costs and enable better treatment paradigms. This approach is especially helpful to improve and streamline the regulatory approval process for investigational therapies that are intended to address unmet medical need in rare diseases.” Su cites the example of Bavencio (avelumab), an immunotherapy developed by EMD Serono and parent company Merck KGaA for the treatment of metastatic Merkel cell carcinoma (MCC), saying: “Bavencio successfully used real-world data as a reference for efficacy, because it’s a rare disease and thus trial enrollment was challenging.”

Similarly, RWE is also making its mark further downstream, to support regulatory submissions and/or later label expansions (for instance, to pursue additional indications, additional patients cohorts or additional clinical endpoints), and to inform negotiations with payers related to formulary placement, drug pricing and the negotiation of value-based contracts or outcomes-based agreements that tie reimbursement rates more explicitly to the performance of the therapy under messy real-world conditions.

“More than ever, drug manufacturers know the trial won’t provide the final evidence package — it’s just the first part of the entire package — and they know that the strategic use of RWE can enable a deeper understanding of value,” says Sarah Alwardt, PhD, VP of HI and HEOR Operations at McKesson, adding: “Since everyone understands that clinical trial findings are limited, there’s a huge appetite for these types of retrospective studies using RWE. It’s a change in mindset that’s very exciting.”

The expanded use of RWE is already helping different stakeholders at different points throughout the biopharmaceutical product lifecycle to expand and calibrate their understanding of the actual clinical effectiveness, long-term health outcomes, cost impact and risk/benefit ratios for various therapies, says Britton of Parexel International, who notes that the growing list of RWE-informed efforts includes:

Identifying new drug targets and better biomarkers

Finding new uses for existing and late-stage products

Identifying undiagnosed, underdiagnosed and misdiagnosed illness

Identifying sites with higher enrollment probability and capability to aid clinical trial recruitment

Predicting patients who have higher risk for adverse events

Predicting medication compliance (or lack thereof) in defined patient cohorts (which can inform mitigation efforts)

Using AI and machine-learning techniques to recognize trends and patterns in social media and healthcare sensor data (to inform clinical study development and define study objectives, patient-relevant endpoints and study procedures)

“Postmarketing studies using RWE are more common now than ever,” notes Michael Fronstin, GM, Real World Evidence, Kantar Health. “Early signal detection through observational studies of newly approved medications is critical to minimizing the potentially broad impact of an unforeseen risk, should a new drug prove to be unsafe within certain patient cohorts.”

Eli Lilly’s new compound, Engality (galcanezumab-gnlm), is expected to receive FDA approval by the end of 2018 for the treatment of migraine headaches. To further understand the burden of migraine and the barriers that preventive and acute treatment options face, Eli Lilly recently announced a study dubbed the ObserVational Survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME). According to the company, this two-year study will be the largest of its kind in migraine, gathering real-world data from 40,000 patients. [3]

By design, the patient population enrolled in any given clinical trial is limited, with targeted patient cohorts handpicked using strict inclusion and exclusion criteria, and enrollment tending to favor younger, healthier patients compared to the entire population in that disease category. Similarly, trial investigators are typically given formal training and required to follow consistent protocols for drug administration and data collection. Collectively, these factors help to greatly reduce variability as the clinical trials are carried out, and thus allow the investigational therapy to show its best self, in a trial population for whom co-morbidities and drug adherence issues have been eliminated or minimized.

By contrast, “when you have someone who is not being studied and poked and prodded in a highly controlled clinical trial, their outcomes will be different,” says Alwardt of McKesson. “By studying data from realworld prescribing, you can dig into which factors are helping to drive improved outcomes in specific patient sub-populations. In other instances, the outcomes will be worse and you can try to identify and reconcile the issues (such as co-morbidities, drug-drug interactions, dosing, complex-administration or adherence issues) that may be to blame.”

“Historically, clinical trials have been primarily focused on efficacy and safety, but in recent times clinical effectiveness has risen as a key differentiator to be studied in the trial,” adds Kantar Health’s Fronstin. “Effectiveness comes in many forms, but is often associated with patient outcomes, which may be clinical, humanistic or economic in nature.”

“Real-world data, such as patient-reported outcomes (PROs), quality of life, disease progression and epidemiology, exposure patterns and factors driving reffectiveness, can inform which parameters need to be captured in the trial design,” says Billy Amzal, MSc, MPA, PhD, SVP, Real World Decision & Data Analytics, Analytica Laser, a Certara company. “Patient registries and social media through opt-in surveys offer a good source of such patient preference data.”

“The patient’s perspective and preferences, captured through PROs, play a particularly important part of demonstrating value in rare diseases and childhood disorders, and focus groups involving patients and other stakeholders such as nurses and physicians, patient association members and caretakers) can help to elicit what types of attributes the drug maker should be looking for when designing the trial, adds Sumeet Bakshi, MBBS, MBA, VP, Real World Data Solutions at Analytica Laser. However, he adds “We find a lot of drug manufacturers coming to us very late in the design phase of a clinical trial, asking for us to identify the most relevant PROs.”

“To incorporate PROs into trials, drug developers are analyzing real-world data to identify specific patient populations that may be experiencing incremental burden or negative health outcomes as a result of their disease,” adds Fronstin of Kantar Health. “Using this insight, patient-reported outcomes can help to shape the trial design.”

Similarly, while the drug’s ability to demonstrate a favorable risk/benefit profile within this limited patient cohort is sufficient to earn regulatory approval, this traditional approach often leaves more questions than it answers, in terms of whether the approved drug can be used in other patient cohorts that were not involved in the trials (such as pregnant women, elderly or pediatric patients, those with renal or hepatic impairment, those with unstudied co-morbidities and so on). In the absence of trial-derived data, physicians are then left to prescribe drugs off-label. This raises potential clinical and ethical concerns for physicians (due to a lack of comprehensive data), and often creates a situation where insurance coverage is restricted or denied, leaving patients to manage the entire cost burden of treatment.

“There are conversations happening today that have never happened before, and in clinical trial design, there is increased appetite among both drug developers and regulators to better understand that RWE can help improve trial design,” says Alwardt of McKesson. For instance, she notes that “In oncology in particular, one of the clinical trial endpoints is almost always progression-free survival (PFS), but PFS is really hard to measure in the real world due to variation from doctor to doctor in terms of how they evaluate and capture such data.” Instead, getting more relevant, real-world endpoints into the clinical trial design will help to create a more powerful trial baseline and more realistic expectations for how the drug will perform once it enters the market.

Innovative value-based contracting or risk-sharing agreements — formally called risk-based contracts or outcomes-based agreements — have been explored for a growing number of high-cost specialty medications. Such innovative contracting arrangements provide a mechanism for biopharma companies and health insurers to both put more skin in the game when it comes to managing the high cost or risk of today’s specialty therapies. Such arrangements aim to tie contracted drug prices and reimbursement rates more closely to actual clinical outcomes that are demonstrated by collecting and analyzing RWE from clinical practice. “The whole idea is to manage uncertainty at the time the manufacturers are committing to a given clinical performance for their drug and payers deciding for a price and reimbursement,” says Amzal of Analytica Laser.

According to Deloitte, 14 of the 20 companies polled in its 2nd annual RWE Benchmarking Survey are currently engaged in value-based contracting, although many industry observers note that drug companies and payers have tended to remain tight-lipped about publicizing such agreements, hoping to preserve their own competitive advantage. Such secrecy thwarts the sharing of lessons learned, and undermine efforts to create a consistent framework or best practices to improve the data collection and expectations and to guide the complex negotiations that are needed to create a win-win for both sides through these innovative contracting schemes.

While interest in and use of RWE throughout pharma and healthcare continues to grow, many industry observers have expressed concern and frustration over the inherent variability and inconsistency of the RWE data sources that are increasingly being pressed into service. Such challenges, according to Britton of Parexel include:

Heterogeneous data and lack of interoperability

Data incompleteness, inconsistency and inaccuracy

Data ownership and data-use agreement status

Data privacy regulation / patient-level authorization / ongoing patient consent management for RWD usage

Lack of standard unique patient identifiers to enable linking across data sources

Multiple data sources and the need for ‘big data’ aggregation and ‘data lake infrastructure’

Shortage of biomedical and informatics expertise to successfully leverage modeling, simulation and AI opportunities

Similarly, Bakshi of Analytica Laser notes investigators must be aware of the limitations of the available data, and design any studies accordingly. “Claims data was set up to manage insurance claims — it was never intended to be used for conducting comparative effectiveness studies, but many are doing that today, so you have to identify the gaps and limitations.”

Many are calling for some type of industry standards or guidelines, to establish some criteria for data consistency.

“The lack of comprehensiveness, consistent quality and standardization threatens to undermine trust and limit the full potential of using RWE to advance many objectives in pharma,” says Doyle of IQVIA. “Today with so many parallel efforts, the use of RWE is being democratized, which should prompt research design innovation, but how do you validate and pressure-test the various approaches for validity and reliability? I am eager to see what type of guidance FDA ultimately issues with regard to RWE guidance.” He notes that FDA’s 2017 guidance issued on the use of RWE in the field of medical devices [4] provides a lot of hints about FDA’s thinking on this topic.

Additional industry-wide initiatives are already underway to address some of these challenges. For instance, in 2017, the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) created a joint task force which is working to establish consistent methodologies and procedural practices to improve the consistency and reliability of using RWE [5]

Similarly, the GetReal Initiative (www.imi-getreal.eu), established in 2013 by an EU public-private consortium consisting of pharmaceutical companies, academia, HTA agencies, regulators and patient organizations, is a working to develop a variety of tools and resources for RWE.

Second Annual Real-World Evidence (RWE) Benchmarking Study, 2018, www.deloitte.com/insights

https://www.asco.org/advocacy-policy/asco-in-action/fda-limits-use-tecentriq-and-keytruda-some-urothelial-cancer-patients

https://investor.lilly.com/news-releases/news-release-details/lilly-announces-initiation-observational-survey-epidemiology

FDA, Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices, issued August 31, 2017; https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm513027.pdf

Berger, Marc., et al., Good Practices for Real-World Data Studies of Treatment and/or Comparative Effectiveness: Recommendations from the Joint ISPOR-ISPE Special Task Force on Real-World Evidence in Healthcare Decisionmaking,

The widening scope of RWE data available from patients is changing both clinical and post-approval practices for drug development

Real-World Evidence (RWE): Advancing Both Clinical and Commercial Objectives

 had a prominent position in the biopharma industry, as well as healthcare generally, because the stakes are so high: cancer is often fatal; in its many forms, it is a common health condition; and, in recent years, the reimbursement for successful therapies is sizable. New medical science, notably in immuno-oncology (I/O)therapies that employ the body’s own defense mechanisms, is energizing the field. The rapid pace of development, though, is stressing all parties involved: researchers, payers and oncologists. Researchers are proposing new treatment pathways—“stacking” one therapy on top of another; antibody combinations; and crucial companion diagnostics to determine treatment suitability.

Heartbreakingly, while more than a few new therapies show signs of what is a fraught word in cancer—a “cure”—those therapies have already been shown to work well for a fraction of patients—perhaps 30%—and of little or no value to the rest. Side effects can be severe in some cases. All this will put a larger burden on manufacturers and healthcare providers in developing real-world evidence (RWE) during drug development, and massive physician and patient education and follow-up during treatment.

One of the most vexing aspects of cancer cells is that they often exhibit a fiercely atavistic ability to evade recognition by the body’s own immune system, essentially preventing the immune system from recognizing them as malignancies. The leading forms of I/O therapies all manipulate cancer cells or immune cells in ways that allows the patient’s own body to attack and kill off the cancer cells lurking within.

“It is difficult to overemphasize the impact of these innovative agents in the treatment of a wide variety of cancers, and we are now experiencing a broader acceptance of immunotherapies in the first-line setting,” says Kasia Shields, PharmD, director of oncology medical communications at Xcenda (Palm Harbor, FL). “With its potential to offer more beneficial and safer cancer treatment, I/O is now viewed as the ‘fourth pillar’ of oncology treatment, alongside the pillars of surgery, radiation and chemotherapy.”

 Data from a national survey by Cancer Treatment Centers of America[/caption]

“Oncologists have long shared the dream of harnessing the immune system and addressing corrupted parts of the immune cycle to fight cancer. For many, the surge in I/O activities and the arrival of approved I/O therapies has felt like the dawn of a new era—and a dream come true—in the cancer-treatment paradigm,” adds Malik Kaman, associate principal, ZS Associates (Zurich, Switzerland). “Indeed, we’ve all gone a bit ‘I/O crazy’ lately, but there are some good reasons for this.”

Specifically, in recent years, I/O breakthroughs have been hotly sought in the areas of checkpoint inhibitors (such as CTLA-4, and the PD-1 and PD-L1 therapies), engineered T-cells (such as chimeric antigen receptor modified T-cells or CAR-T, therapies), bi-specific antibodies, monoclonal antibodies, and a few others. “The advantage to all of these approaches is that they train your body’s natural immune system to simply do its job better. In layman’s terms, they strip away the disguises that cancer uses to hide from the immune system,” Kaman adds.

“Immunotherapy in oncology is already providing results in several malignancies that have been difficult to treat in the past, which is exciting,” says Pamela Crilley, DO, Chair, Dept. of Medical Oncology at Cancer Treatment Centers of America (CTCA), and Chief of Medical Oncology, Eastern Regional Medical Center (Philadelphia, PA). Today, FDA-approved immunotherapies are available for a growing list of diseases, including melanoma, non-small cell lung cancer, certain lymphomas, head and neck cancer, and bladder cancer.

“I/O approaches hold tremendous promise for patients with cancer, although we are still in the early days of this field and there is still much to learn about the broad applicability of them in oncology practice,” adds Richard Gregory, PhD, EVP and chief science officer for ImmunoGen (Waltham, MA), which is working to develop and commercialize a novel therapeutic option called antibody-drug conjugates (ADCs). ADCs are not themselves an I/O therapy but work in conjunction with I/O therapies to promote therapeutic activity.

To date, ADCs have proven themselves to be particularly effective, with several ADCs approved by FDA for the treatment of different cancers, according to the National Cancer Institute (NCI). These include Kadcyla (ado-trastuzumab emtansine) from Genentech, Adcetris (brentuximab vedotin) from Seattle Genetics, and Zevalin (ibritumomab tiuxetan) from Spectrum Pharmaceuticals.

ImmunoGen’s lead ADC, mirvetuximab soravtansine, targets tumor cells expressing the folate receptor alpha (FRa). “We, along with Ventana, have developed a companion diagnostic assay which we use to select patients that are more likely to respond to therapy because their tumor cells express FRa,” says Gregory of ImmunoGen. “This targeted approach to therapy allows us to focus on patients most likely to respond to our therapy and reduces the likelihood that patients without the potential to respond will be exposed to our drug, which has both patient and cost benefit.”

“The type of I/O that is generating the most excitement are the immune checkpoint inhibitors, particularly PD-1 and PD-L1 inhibitors, which are so-called immunomodulatory monoclonal antibodies (mAbs) that work by “taking the brakes off” of immune cells allowing them to do their normal function against cancer cells,” explains Charles Lance Cowey, MD, oncologist with Texas Oncology (Dallas, TX), and member of The US Oncology Network Developmental Therapeutics Research and Genitourinary Cancer Research Committees.

Meanwhile, the data for another form of I/O therapy—using so-called CAR-T cells—has been impressive across a number of different tumor types, but most especially metastatic non-small-cell lung cancer (NSCLC) and metastatic melanoma, and more recently in bladder, and head and neck cancer.

One of the things that sets all I/O therapies apart is that it has the potential to induce long-lasting, durable responses in patients—without the need for long durations of ongoing therapy. “And while immunotherapy treatments do have toxicities, the side effect profile tends to be more tolerable compared to traditional cytotoxic chemotherapy, particularly in terms of issues that affect quality of life,” says Cowey of Texas Oncology. By contrast, many industry observers note that, for the most part, the side effects of I/O therapies are mild and tolerable, especially the existing biologics that are based on the mAbs.

Most appealing about the many I/O approaches that are available or under development is that they demonstrate impressive efficacy in difficult-to-treat cancers, which have been resistant to traditional treatment options, such as metastatic melanoma. “The I/O approach using targeted therapies or checkpoint inhibitors offers the possibility of coming close to the goal of precision medicine, in terms of marrying effectiveness with low toxicity,” notes Dana Evans, MD, Director, Medical Affairs Payer Access, Genentech (San Francisco, CA) 

[Editor’s note: Evans’ remarks reflect his personal views and not those of Genentech]

. “The key upside is that patients who do respond tend to have a longer duration of response—that’s why people are excited about it.”

“However, it’s not without its own challenges, and it’s certainly not a panacea for the treatment of all cancers.” Evans continues. “There are still many non-responders, resistance still develops over time in some patients, and to date, it’s been hard to figure out the companion diagnostic piece of it.”

“It is also clear that the profound responses seen in some cancers (for example, in melanoma patients) do not necessarily extend to all other types of cancer—that is, response rates can vary significantly and probably reflect how visible a particular type of tumor is to the immune system in the first place,” notes Gregory of ImmunoGen.

“Despite the understandable excitement, stakeholders agree that I/O therapies are far from ‘miracle drugs,’ as many patients—70% by some estimates—will not respond to them at all,” adds Shields of Xcenda. “This is forcing oncology as a whole, including manufacturers in the I/O therapeutic space, to shift away from any one-size-fits-all treatment model, and to instead seek the most effective ways to distinguish those patients who would actually benefit from newer treatment modalities.”

As a result, stakeholders agree that the future success of I/O therapies in oncology will rely heavily on identification of improved biomarkers, and protocols that combine I/O therapies with traditional chemotherapies and newer biologic oncology agents. As there are dozens of new drugs in development to modulate the immune environment in a variety of ways, this leads to an exponentially high number of combinations and sequencing opportunities.

“This surge in treatment candidates calls for novel and adaptive clinical trial designs—including studies that use serial tumor biopsy sampling and selection of enriched patient populations for immune targets—to help guide the effort,” says Cowey of Texas Oncology. “The staggering cost of drug development makes appropriate trial design and drug utilization a high priority, especially in markets that are increasingly competitive and crowded.”

To wit: According to 2015 data from IMS Institute for Healthcare Informatics (Parsippany, NJ), the annual growth rate in cancer drug costs has risen from 3.8% in 2011 to 11.5% in 2015, at constant exchange rates. In the US, cancer drugs now make up 11.5% of total drug costs, up from 10.5% in 2011.

“Drug makers must think through how to position their novel I/O therapies (front-line, relapse, maintenance, or all of these),” says Chadi Nabhan, MD, VP and chief medical officer, Cardinal Health Specialty Solutions (Dublin, OH).

Similarly, perhaps unlike other oncology therapy approaches, “the key thing is to know when and how to apply I/O therapies for best effect,” adds Dr. Robert Rifkin, oncologist with Rocky Mountain Cancer Centers (Denver), a practice in The US Oncology Network. “I/O approaches will likely work best with patients with some immune system that can still be reprogrammed. Similarly, if the patient’s immune system is too damaged, they will not be as effective and the cost of the approach may not be justified.”

The two most well-known commercial I/O products—Merck’s Keytruda (pembrolizumab), approved for melanoma, NSCLC ,and some head and neck cancers, and Bristol-Myers Squibb’s Opdivo (nivolumab), approved for NSCLC—both use humanized antibodies that block PD-1 (a protective mechanism on cancer cells that help them evade detection by the immune system). In essence, these therapies rip the proverbial ‘cloak of invisibility’ off the cancer cells, allowing the body’s T cells to actively attack them. Both rely on companion diagnostic testing to identify the most receptive patients in each of the approved indications.

Meanwhile, Genentech/Roche’s Tecentriq (atezolizumab), approved last October, was the first FDA-approved checkpoint inhibitor that is focused on the anti-PD-L1 pathway instead of PD-1, and is approved for use with bladder cancer and metastatic NSCLC.

The ligand PD-L1 is a protein that is expressed on cancer cells and immune cells; anti-PD-L1 antibodies bind to the PD-L1 ligand and undermine the ability of tumor cells to use PD-L1 for protection against white blood cells, such as human T-cells from the immune system — thereby allowing the immune system to take the tumor cells out more effectively. In a nutshell, in the words of the National Cancer Institute (NCI): “Immunotherapies either stimulate the activities of specific components of the immune system, or counteract signals produced by cancer cells that suppress immune responses.”

In March, the latest human PD-L1 antibody—Bavencio (avelumab) from EMD Serono (the US biopharmaceutical business of Merck KGaA) and Pfizer—won FDA approval for the treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer with fewer than half of patients surviving more than one year and fewer than 20% surviving beyond five years. The companies reported that Bavencio produces durable tumor responses in mMCC patients, with 86% of responses lasting at least six months (n=25), and 45% of responses lasting at least 12 months (n=13). Duration of response ranged from 2.8 to 23.3 months.

“With the approval of Bavencio for the treatment of mMCC, we now have seven approved oncology indications for PD-1 and PD-L1 checkpoint inhibitors, and we expect to see another five to eight different oncology indications being addressed in the next round of checkpoint inhibitor approvals,” says Herman Sanchez, partner, Trinity Consultants (Princeton, NJ).

“Both categories of checkpoint inhibitors (the anti-PD-1 and anti-PD-L1 therapies) rely on the same pathway—checkpoint inhibition—but are coming at it from a different direction,” says Evans of Genentech. “Developers are targeting the right pathway, but the companion diagnostics are just not precise enough to effectively target the right patient right now.”

“There are currently five molecules under development that appear to offer relatively similar efficacy and safety tradeoffs,” says Kaman of ZS Associates. As of this past summer, there were more than 700 ongoing trials for the main PD-1 and PD-L1 checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab, avelumab and durvalumab). Of these trials, more than 200 were for Phase I or II programs involving 100 or more patients. “This signifies a big shift in the way we think about bringing these drugs to market. It also denotes a massive arms race to be first-in-class in new indications.”

Later entrants to the space will face greater challenges to differentiate themselves to physicians and providers. “If a particular I/O will be third or later launching in a given tumor type, manufacturers must pass a higher bar and find meaningful ways to gain payer coverage,” says Kaman. “The trend is toward faster, more efficient trials, followed by RWE to prove it’s working. The key is to break the cycle of adversarial negotiations that can prevent faster and more meaningful progress on this topic.”

Since the aim of immunotherapy is to “exaggerate” the immune response against cancer, it can, unfortunately, also elicit unwelcomed inflammatory and autoimmune side effects, so managing these risks will be an important issue as I/O therapies become more widely used,” notes Shields of Xcenda. For instance, among the warnings and precautions stated for EMD Serono/Pfizer I/O therapy Bavencio are such immune-mediated adverse reactions as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction. Many of these are associated with other checkpoint inhibitors as well.

“Interestingly and not surprisingly, there is a growing interest among patients who want to know more about the ability to train the body’s immune system to fight the disease, but unfortunately their oncologists are not talking about it with them,” says Crilley of CTCA. In general, patients and other stakeholders may not be fully aware of how immunotherapy works, or be aware of the early- and late-term side effects. Patients, caregivers and providers need to be educated on immunotherapy treatment in order to facilitate patient-provider discussions. Manufacturers can play a leading role in this initiative.

 by CTCA in February, the 2017 Cancer Experience,* “More than two-thirds of cancer patients and their caregivers have limited knowledge of the latest treatments to help inform their treatment decisions; 74% of cancer patients expressed interest in learning more about immunotherapy, yet only 32% say their oncologist has discussed immunotherapy with them,” says Crilley.

"Patients and caregivers frequently don't know what questions to ask, especially after an initial diagnosis, and they typically default to the Internet to obtain additional information," said Maurie Markman, MD, president of medicine and science at CTCA, at the time of the announcement. “Much of this is difficult for them to interpret, however, so an increasingly important part of our responsibility is to help them understand what they have seen or read, and its possible relevance to their treatment options.”

Another I/O modality that is different from checkpoint inhibition is the use of modified T cells (CAR-T)—which thus far has no approved therapies yet, but is eagerly anticipated as regulatory approval of the leading candidate is expected in the near future. “This modality is generating significant interest and excitement from all stakeholders as CAR-Ts have shown activity in relapsed lymphomas, acute lymphoblastic leukemias, and chronic lymphocytic leukemia,” say Nabhan of Cardinal Health. However, he notes that “the toxicity of CAR-Ts can be severe and careful attention to how these adverse events should be managed is essential to assure favorable outcomes to patients.”

Worldwide spending on cancer medicines will exceed $150 billion by 2020, up from $107 billion in 2015 according to recent data from IMS. “Cost is clearly the most pressing issue associated with I/O therapies, and stakeholders agree that manufacturers need to demonstrate the value of this modality in a changing reimbursement landscape where cost containment and maximizing efficacy is a paramount concern to payers,” says Nabhan of Cardinal Health.

“The best way to position a new agent among its competitors and maximize payer coverage is to know which patients are most likely to receive response with the agent, and then gearing studies toward that population. This requires good science and thoughtful trial design, and is certainly one of the main challenges facing the I/O community over the next decade,” says Cowey of Texas Oncology. Today, cancer researchers are pursuing both traditional and non-traditional biomarkers, including “tumor neoantigen profiling,” “mutational load analysis,” and identifying certain infiltrating immune cells within tumors, to improve the deployment of checkpoint inhibitors.

“Combining checkpoint inhibitors with older or generic chemotherapy may not drive up costs as dramatically, but once you combine two immune therapies, with a biologic or a newer non-biologic specialty drug—so-called stacking—that’s going to create enormous cost issues,” adds Evans of Genentech.

Clearly the argument can be made that using a combination of therapies in search of the most advantageous synergistic effects to drastically improve outcomes represents money well spent, to get the patient into remission or even cured and back into their productive lives, where they are living longer lives, supporting their families and so on. Many believe that there will always be a tipping point where really effective treatment—or even cures—can help justify huge price tags. But it helps to back up such claims with real-world evidence.

“Consider the use of Yervoy and Opdivo in combination to treat melanoma—the cost can easily run to $200,000. While Bristol-Myers Squibb is offering a discount for patients who use both therapies simultaneously, it’s important to note that the costs aren’t necessarily hitting the patients—they are falling on the backs of the payers and the drug companies, who shoulder much of the high cost,” says Sanchez of Trinity Consultants. That’s why there’s keen interest in making sure only the right patients are getting these costly therapy options, and helping to manage the affordability. “Drug makers do not want to risk headlines of patients abandoning promising therapy options because of the cost, so RWE data (which is always messy due to poor adherence and tolerability issues) must be developed to drive the most appropriate utilization.”

Despite the hurdles, some expect growing competition in I/O to help keep costs down. “We now have a lot of different I/O products being pursued. This is already seeming to bend the cost curve for new drugs developed under the bio umbrella, where we may be seeing a 10% price premium, over traditional therapy options—not a 25% price premium,” says Sanchez. “As multiple I/O drugs are racing to the finish line, the competition should favorably impact the starting costs that were common just a few years ago.”

One promising combination is the use of ADCs (to shrink or “de-bulk” the tumor and prime the immune system) in conjunction with I/O therapies. “When the promise of this combination is realized, then the length and quality of life that patients might achieve should justify that cost,” says Gregory of ImmunoGen.

More than ever, reimbursement is contingent on showing value of a particular therapy where value is broadly defined as outcomes divided by cost. “RWE studies and patient-reported outcomes that can show how efficacy and quality of life are potentially improved for patients when I/O therapies are administered and used under real-world conditions are becoming essential in payers’ determination of favorable coverage,” adds Nabhan of Cardinal Health.

“Due to the high cost of immunotherapies, manufacturers need to proactively engage payers and other stakeholders early on in cost-effective discussions and leverage various value frameworks to communicate a comprehensive value story of these innovative therapies,” says Shields of Xcenda. “Similarly, patients may face exorbitant out-of-pocket costs, so in addition to traditional foundation programs, it will be imperative for pharma companies to establish far-reaching patient-assistance programs (PAPs) that can help to offset those costs.”

“Oncologists are already overwhelmed. Many of the physicians we contact in research today have difficulty differentiating the drugs or even assigning the right molecule to its appropriate mechanism of action,” says Kaman of ZS Associates. In this context, developers will have to find alternative ways to differentiate beyond just proselytizing their data.”

“Manufacturers have an opportunity to play a strong leadership role,” Kaman adds. “Leading manufacturers must work in partnership with payers, hospitals and physicians to run pragmatic trials and generate real-world evidence that shows where these therapies work the best and where they do not.”

Meanwhile, the visible role of so many competing value frameworks within oncology—such as those developed by the Institute for Clinical and Economic Review (ICER), the National Comprehensive Cancer Network (NCCN), Memorial Sloan Kettering Cancer Center, and the American Society of Clinical Oncology (ASCO) — is also helping to shape the topography within the I/O space. John Doyle, SVP, Real-World Insights, QuintilesIMS (New York, NY) notes that many of today’s value frameworks are more amenable to meeting with drug developers earlier in the process, to have conversations about competing methodologies that may help to demonstrate value. “The conversation goes increasingly beyond just clinical attributes (safety, efficacy, administration) and cost issues—drug developers are thinking about many other aspects of the patient experience, including humanistic elements, and baking them into the clinical-development program earlier in the process,” he [Doyle] notes. “In fact, we’re seeing clinicians, epidemiologists and I/O statisticians on clinical-development programs, all worrying about the parameters that the value frameworks value, and simulating what that will look like as early at Phase II, to maximize the probability of success with FDA and EMA.This is all very new—and I’ve been in the oncology space for more than 20 years.”

When it comes to showcasing an I/O therapy’s full value proposition, Doyle of Quintiles says he finds it fascinating that some pharmacos are actually simulating what the potential “value framework” scores might be for their new I/O therapies much earlier in the process—as early in Phase II. Such efforts can help to shape future clinical development work, to better showcase safety, efficacy and administration in the I/O space, helping drug developers to study things that don’t show up in the clinical trials, such as patient costs, societal costs and non-traditional patient metrics, in parallel, so the companies have all the evidence they need to tell holistic story right from the outset.

“Similarly, there are concerns around the perception that ‘you must try I/Os on patients to see if they truly work’ which usually necessitates a 90-day trial at a substantial cost,” says John Kalada, a senior director at Xcenda. “The case for trying it is made stronger when an approved biomarker is present—then the plans are generally more confident they are getting appropriate value for their investment via a very targeted approach.”

“At present, there are 190 oncology practices and 16 payers participating in the risk-reward-bearing Oncology Care Model (OCM),” says Kalada. “The recent clarification around FDA’s FDAMA-114 statute [which was designed to allow companies to more readily disseminate healthcare economic information (HCEI) to those who need it during formulary development] will create an open environment for greater use and dissemination of this level of real-world evidence that is focused on clinical and financial outcomes.”

An ‘overwhelming’ information load is affecting oncology’s ability to develop successful treatment pathways

New science energizes the cancer market

As the graying of America continues unabated, seniors now represent 14.5% of the US population—one in seven Americans. The oldest Baby Boomers are turning 70 this year, and according to US Census data, starting in 2011 and continuing until 2030, roughly 10,000 Baby Boomers celebrate their 65th birthday each day. With advanced age comes increased consumption of healthcare services, prescription medications and increased reliance on long-term care (LTC) facilities, including nursing homes, skilled nursing facilities and rehabilitation centers.

The old are getting older, too: By 2050, an estimated 27 million people will need long-term care services and support, up from 15 million in 2000, according to CDC statistics.

These facts have been cited for many years, but what is less noticed is how trends in gerontology are changing the LTC industry, and the pharmacy businesses serving it. Speaking at an investor meeting last spring, Gregory Weishar, CEO of PharMerica, said this “sleepy little business” is evolving as the concept of “age in place” grows widespread: seniors are staying in their own homes longer (increasing the need for home health services), or moving to assisted living facilities (a business growing faster than nursing homes) and a variety of senior communities that provide a higher level of healthcare than in the past.

PharMerica, the No. 2 institutional pharmacy company serving the LTC industry, is addressing these trends by expanding its home infusion service business, and developing a sideline in specialty pharmaceutical services, primarily for oncology products. The No. 1 company in LTC pharmacy, Omnicare, has undergone its own dramatic change, being acquired by CVS Health in 2015. A year later, that action by CVS is already benefitting its bottom line profitability.

Aside from these two market leaders, there are approximately 1,200 independent LTC pharmacies, which operate in much the same relationship to the market leaders as independent community pharmacies do to the chain drugstores. In particular, the bigger firms are consolidating the industry by acquiring the independents; PharMerica alone says it sets aside $100 million annually for this purpose.

Evidence of how contested this arena is becoming can be found in the formation, in 2014, of the Senior Care Pharmacy Coalition, a Washington, DC advocacy group sponsored in part by the major wholesalers who serve the independent LTC pharmacies. It advocates for many of the same issues as independent community pharmacies, such as PBM reimbursements, federal rules on compounding and conflicting CMS guidances.

QuintilesIMS, in its annual Use of Medicines report, pegs pharmaceutical sales to LTC at $16.7 billion in 2015, up only 3% from the year before and well off the overall industry growth of 12.2% (the figure does not include home health; it also represents ex-manufacturer pricing and not the discounting that occurs with most pharmaceutical sales). A major factor in revenue growth is the increasingly tighter reimbursement policies of CMS; besides Medicare itself (which pays for most elderly pharmaceutical dispensing), the Medicare Advantage plans that many insurers offer contain the same formulary lists and reimbursement tiers that put pressure on pharmaceutical revenues for all types of patients.

Per CMS data, there are more than 15,000 skilled nursing facilities (an SNF is a nursing home certified to accept Medicare payments); many are privately held (and around 70% are for-profit), but many are also run by charitable organizations or community health services. And while Argentum, a trade association of senior living communities, counts 7,000 assisted-living, independent-living and memory-care facilities among its membership, there are some 45,000 other senior living facilities in the US.

A senior, residing perhaps at an independent living facility, is likely to go to the local pharmacy or visit a local doctor, just as in younger days. But for most SNFs, some assisted-living facilities and an undetermined number of other living arrangements, the LTC pharmacies are the main source of medications.

LTC pharmacies play a more central role, generally speaking, than retail pharmacy does for general-population healthcare. Because many nursing home residents have limited cognitive skills combined with many comorbidities, there are extensive federal regulations and professional best practices on how their care is managed. Some LTC pharmacies provide the consultant pharmacists that are required to review a resident’s medication regimen monthly, which is designed to ensure that medications are being prescribed for medically valid reasons.

“Consultant pharmacists look at the resident’s overall medication profile to ensure elements such as appropriate indication for a medication, minimization of drug interactions, appropriate medication and lab monitoring, polypharmacy issues, and proper medication administration,” says Kimberly Binaso, PharmD, VP of clinical services at Managed Health Care Associates (MHA), a group purchasing organization for post-acute care facilities. “They also serve as an educator and advisor to the facility, typically serving on various committees and conducting quarterly in-house services on a chosen disease state or regulatory topic.” As such, consultant pharmacists have a key role to validate, challenge and modify the initial drug selections made by the attending physicians and other health practitioners.

The American Society of Consultant Pharmacists (ASCP; Alexandria, VA) counts 8,000 such pharmacists in its membership, including students.

Besides these third-party consultant pharmacists, there are others involved in selecting medicines for LTC residents. These include the prescribing physician or nurse practitioner (who specify the initial prescription), the nursing staff (who are in a position to recognize symptoms that may call for a given therapeutic treatment option to be prescribed), the medical director of the facility, and the pharmacy & therapeutic (P&T) committee members who are responsible for shaping the formularies that will be used by an LTC facility.

Generics occupy roughly the same market share in LTC as in the general population—around 85%. But new therapies are having a profound impact.

“In recent years, the range of medications prescribed in nursing homes and other LTC facilities has been greatly expanded, to include more therapies that are used for the long-term management of chronic conditions such as cancer, HIV, end-stage cardiomyopathy, multiple sclerosis, inflammatory conditions, diabetes, hepatitis C, autoimmune diseases and others, many of which were unheard of in nursing home settings only a few years ago,” says Dr. Richard Stefanacci, DO, chief medical officer at The Access Group (Berkeley Heights, NJ).

While this represents market opportunity, makers of branded therapies know that gaining a foothold in highly regulated class of trade is particularly challenging, thanks to a confluence of complex factors that are at play in the LTC arena. To overcome the many barriers, manufacturers need to deliver strong messaging that underscores the clinical and long-term economic advantages of their branded product particularly with regard to generic competitors in the same therapeutic class. “You really have to sell the full value of your product over the entire episode of care,” says Frank Grosso, RPh, CEO, executive director, ASCP.

“If your brand-name drug is a me-too drug with little discernible benefit over generic, then you really don’t have a sustainable market in LTC—because managing drug costs is the predominant factor when there is no discernible reason to justify keeping patients on the branded therapy,” says Grosso. “Drug companies must demonstrate longitudinal value over the entire episode of care for a brand—that’s a very different way of marketing for pharma companies but creates huge opportunity.”

“Today, roughly 57% of those in LTC settings are Medicare, Medicaid and so-called ‘dual eligible’ patients (those who are covered by both Medicaid and Medicare), while 29% are covered by private insurance, and the remainder are private-pay patients,” says Grosso. He notes that the 57% who have Medicaid or Medicare or are dual eligible don’t have access to all of the 746 Medicare Part D plans that are in existence today. “Rather, they typically only have access to the 231 so-called ‘benchmark plans’ (a subset of the total available Part D plans on the market today),” says Grosso. “The benchmark plans are lower-cost plans with more restrictions in terms of formulary designations and prior authorization restrictions, and in the post-acute setting, the pressure is on for physicians to only prescribe through those 231 benchmark plans to avoid out-of-pocket costs for low-income beneficiaries and skilled nursing centers.”

“It’s not an insurmountable task for brand teams, but it requires targeted effort to get the product on as many of the 746 traditional Part D plans, and the 231 lower-cost benchmark plans, as well,” he adds.

John Doyle, DrPH, MPH, SVP at QuintilesIMS, notes that analyzing the continuum of care for LTC residents is essential to marketing success. “Nowhere is the mantra to make sure the ‘right patient gets the right drug at the right time’ more important than in the LTC setting. It’s extremely important that drugs fit well into the prevailing disease-management protocols and pathways and the individual patient’s overall care plan.” “They should be modeling their products using market research, interviews, electronic medical records and physical chart reviews in concert with the LTC to take stock of what care and risk really looks like today in the LTC setting, and they should be tracking outcomes and correlated cost data,” he adds. “The goal is to simulate ‘what the situation looks like with my product on your formulary.’” He notes that this approach is already being used in some health technology assessments integrated delivery networks (Kaiser Permanente and others) so drug companies “don’t need to reinvent the wheel—they just need to align their approach with the specific challenges and opportunities in the LTC setting.”

Because there are so many HCPs with prescribing authority, including geriatricians, nurse practitioners and physician assistants who also have prescribing authority, pharma companies do well to pay closer attention to all of them. “Pharmaceutical companies are increasingly deploying a dedicated LTC sales force to provide this information directly to LTC health care practitioners and pharmacies,” says Binaso of MHA.

“As the healthcare industry increasingly moves to a pay-for-performance model, LTC pharmacy services become increasingly vital to successful patient outcomes,” Stephen Hendrickson, SVP of sales, community & specialty pharmacy at AmerisourceBergen. Among the value-added services a dedicated LTC pharmacy can provide:

drug utilization review and training for the LTC staff

unit-of-use packaging, such as blister (“bingo”) cards, cassettes and other packaging

specialized drug-delivery formulations and compounding services

manage reports, forms & prescription ordering supplies as necessary for facilities

“Unit-dose packaging, especially, has evolved to become highly specialized and truly makes it easier for patients to access and stay adherent to their medication,” says Hendrickson.

“In addition to providing a range of medication-management services throughout the continuum of care, LTC pharmacies manage medication records, clarify orders, manage emergency medications, provide holistic clinical review, and they package medications in unit doses or in compliance packaging and prepare IV products,” adds Rich McKeon, VP, McKesson’s Alternate Site Pharmacy. “As far as ongoing drug-regimen reviews and ongoing medication management is concerned, LTC pharmacies and consultant pharmacists also play an essential role in terms of quality assurance checks, especially with regard to the use, potential overuse and complex drug-drug interactions that can occur when seniors are taking so many medications, particularly to prevent excessive use of narcotic pain medications, antibiotics and psychotropic medications.”

As with pharmaceuticals in all other healthcare settings, the impact of specialty pharmaceuticals to treat chronic conditions is on the rise in LTC. The Managed Health Care Associates 2016 Independent Long-Term Care Member Study analyzed LTC pharmacy dispensing data nationally from 1,231 pharmacies between 2014 and 2015.

The study shows the “total annual specialty pharmaceutical spend has grown by 59%, and brand specialty pharmaceutical spend grew by 66–67% in each of the last two annual MHA studies,” says Binaso. Specific findings include:

Hepatitis C treatments—25% increase (Note: In the 2015 study, reflecting the period when several hepatitis C treatments were introduced to the market, growth in this category had been 289% that study year)

Multiple sclerosis medications—13% increase

Inflammatory conditions (such as rheumatoid arthritis, ulcerative colitis and others)—37% increase

On the plus side, the MHA study confirms that challenges that limit patient access to specialty drugs—such as limited or preferred distribution and payer networks for today’s costly specialty medications, and the extra burden of compliance with Risk Evaluation and Mitigation Strategies (REMS)—are not necessarily insurmountable in LTC facilities. However, “ensuring access to specialty medications continues to be a major challenge for LTC facilities as LTC pharmacies are often excluded from participating in limited-distribution pharmacy networks,” says MHA’s Binaso. “We continue to see an overall lack of understanding of the nuances of long-term regulations, the patient population being serviced, and transition of care issues by both the pharmaceutical company and their contracted limited-distribution pharmacies.”

Sometimes, LTC pharmacies turn to third-party partners to assist with formulary development. “Typically, long-term care facilities want to work with fewer and a consistent cadre of distributors for all medication, equipment and healthcare products. By working through their distributors to drive product access needs, providers can feel confident that they have optimal access to the products they need in the most convenient setting for their operation/patient care,” says Akin Odutola, SVP, Specialty & Branded Product Access, AmerisourceBergen.

Likewise, McKesson’s PATH Pro is a geriatric formulary-management program for post-acute therapeutics, which “helps LTC pharmacies to reduce inventory costs, standardize care processes and build stronger, differentiated partnerships with skilled nursing facilities,” says McKeon. “The program creates drug formularies from a clinical perspective, taking into account geriatric considerations, such as the physiological changes of aging, drug interactions and side effects profiles that are particular to older patients, in order to help LTC pharmacies to purchase and dispense those products that have the safest and most effective profile and competitive price for the geriatric patient population.”

In addition to determinations for drugs that should be on preferred drug lists across 20 therapeutic classes, the McKesson service provides easy access to clinical research and independent review of safety profiles, up-to-date safety warnings and monographs related to individual drugs, helping facilities to reduce prescription drug costs and standardize medications across all of their facilities.

“With a credible preferred drug list developed specifically for geriatric patients, consultant pharmacists are in a better position to standardize drugs across multiple facilities, which helps pharmacies with inventory forecasting and cost reduction,” adds McKeon of McKesson. “Clinical studies that indicate increased safety or efficacy of the brand medication could potentially be very beneficial.”

Today, the vast majority of patients in nursing homes and other LTC settings are “dual eligible” patients, meaning they are enrolled in both Medicaid and Medicare. Typically, Medicare acts as the primary payer for a range of services; Medicaid provides cost-sharing assistance and may pay for services that are limited or not covered under Medicare.

“The long stay is covered under Medicare Part D, and each Part D plan has its own formulary that is well outside of the nursing home's control,” says The Access Group’s Stefanacci. “Medicare Part A provides drug coverage during the subacute/short stays (Medicare pays a per diem to the nursing home that includes all medications). “As a result, skilled nursing facilities develop their own formulary drugs prescribed under Part A.” This complicates the picture when it comes to drug companies trying to ensure access to its products across all of the many competing formulary types.

One issue to watch is the changing status of the so-called “protected classes” that were identified when Medicare Part D was initiated. Today, all Medicare Part D plans are required to include therapy options in these six categories—antineoplastics, anticonvulsants, antiretrovirals, antipsychotics, antidepressants and immunosuppressants. “Part D Legislation designated these protected classes to ensure that Medicare patients would have access to these life-saving therapies,” says Stefanacci of The Access Group. “Recently CMS has been given permission to eliminate some of these requirements, and this could limit patient access to some medications that are already heavily utilized by patients in LTC facilities.” Specifically, the Medicare Payment Advisory Commission (MedPAC) recently recommended eliminating two protected drug classes—antidepressants and transplant medications.

At all types of LTC facilities, the pressure is on to reduce hospitalization, and for short-term stay patients, to reduce readmission to the skilled nursing or rehab center. An often-cited 

 shows reducing hospitalizations and emergency room visits by 25% among Medicare beneficiaries living in LTC facilities could have reduced $2.1 billion in healthcare costs in 2011 alone. These savings come from the high cost of acute care, and the potential for medication errors and hospital-acquired infections that can occur during a hospital stay, particularly among the frail-elderly, says Stefanacci. Similar studies have suggested that a 33% reduction in potentially avoidable hospitalizations would save Medicare more than $1 billion annually.

As a result, LTC facilities continue to face mandates from the CMS to reduce hospitalizations and readmissions to skilled-nursing and rehab facilities. CMS estimates that roughly 45% of hospitalizations among Medicare/Medicaid enrollees receiving either Medicare skilled nursing facility services or Medicaid nursing facility services could have been avoided, saving billions of dollars in healthcare expenditures.

Today, “targeting those LTC facilities that are discharging the most patients to home (such data are available on the CMS website) should be a strategic business focus for those providing therapies for chronic conditions such as heart disease, diabetes, COPD and others,” says ASCP’s Grosso. “Today a typical short-stay nursing home with 100 beds may have an average length of stay of 20 days. Such turnover means that 150 patients per month are being discharged to home. Compared with longer-stay LTC setting, these facilities are producing a larger target patient population who may benefit from the strategic adherence factors, outcomes data, and safety and clinical advantages that the branded drug may be able to provide at home—in other words, that the drug should not be judged on its price alone.”

“To reduce costs and improve the patient experience and outcomes, CMS is calling for efforts to coordinate care earlier in an effort to avoid hospitalization earlier, or if hospitalization is necessary, there should be a better transfer of information for an improved patient care plan in an effort to reduce adverse events,” adds Doyle of QuintilesIMS. The right medications can play a big role here in reducing hospitalization and readmission.

A case in point that Doyle cites is Entresto, the branded ACE inhibitor from Novartis. He says that the drug has been proven to reduce congestive heart failure (CHF)-related hospitalization. “LTC facilities are very much focused on which drugs could help to avoid or reduce the length of stay—and such clinical advantages may help to address cost differentials over generic alternatives,” he says.

“Under current and proposed Medicare rules, nursing homes and hospitals will continue to be financially penalized for excessive hospital readmissions,” says Grosso of ASCP. “So it begs the question for them: ‘Should we put the patient on the higher-cost therapy (that may prevent readmission), or should we save money in the short term on generics but then face penalties later?’” As the debate continues over whether it’s more prudent to opt for the lowest-cost drug, or to pay the higher cost of a branded therapy with data that supports reduction of overall episode-of-care costs, says Grosso, “It’s more important today than ever before that pharmaceutical manufacturers and healthcare providers work collaboratively to focus on the patient’s episode of care and consider the most cost-effective drug therapy rather than the lowest-cost drug.”

The ‘age in place’ trend creates challenges for market access to seniors

Targeting the gatekeepers in long term care

Despite their moniker, rare diseases are anything but rare when taken in the aggregate. By definition, a rare disease, often genetic in nature, is chronic, life-threatening and impacts fewer than 200,000 people in the US, or five per 10,000 in the European Union. Today, more than 7,000 rare diseases have been identified, and collectively, they impact 30 million Americans (about 1 in 10 in the US population). Half of those affected worldwide are children.

More than 500 orphan drugs have been approved for the treatment of rare diseases since the passage of the Orphan Drug Act (ODA) in 1983, and the pace is quickening. Over the past decade, more than 230 new orphan drugs have received FDA approval. In 2015, FDA approved 21 novel drugs with a rare-disease designation, out of 45 new drugs overall.

Existing incentives continue to draw in new drug developers; payers begin to look at competitive markets to drive down drug costs