A 2 0 1 6 P R E V I E W

Nine Evolutions in Clinical Research and Patient Recruitment

Sandra R. Lottes, PharmDVice President, Global Clinical Development & Operations

Klaira McIntireAssociate Director, Patient & Physician Services

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

his is an exciting time in the biopharmaceutical industry. Increasingly, resources and regulatory processes are being focused to drive new drugs to market within the fastest timeframe. In 2014, the FDA approved 51 new therapies, including 27 to treat specialty conditions, the most since the all-

time high of 53 approvals in 1996. Specialty drugs to treat rare conditions and complex diseases such as cancer have accounted for the majority of FDA approvals in the past four years as drug manufacturers devote more time and money to developing specialized treatments.

Fast Track and Breakthrough Therapy designations are designed to speed the development of promising new drugs intended to treat serious conditions with unmet medical needs. Almost half, 19 of the 41 novel new drugs approved in 2014, were designated as Fast Track, Breakthrough, or both1.

Currently, 7,000 potential drugs are in the development pipeline, and 2015 is on pace to see another record number of approvals. More than ever before, pharmaceutical manufacturers are asked to do more in less time, with tighter budgets, and with much greater competition.

The Intersection of Patient Engagement & TechnologyToday’s patients are educated about their health and are proactive in connecting with other patients facing similar medical diagnoses. Advances in personal health technology in the form of wireless monitoring devices, mobile applications, and electronic patient reported outcomes programs, just to name a few, are offering patients unprecedented opportunities to take ownership of many decisions once made only by healthcare professionals. In addition, these advances are challenging pharma manufacturers to reach patients where they are — often far from research sites.

Keeping Up with Rapid ChangeAs a global service provider, UBC collaborates with manufacturers from the early stages of protocol design through product commercialization. Increasingly, study sponsors are focused on the patient experience in a clinical trial, considering the patient’s lifestyle and demographics, the potential burden of the study visit schedule and assessments, administrative methods of the drug, and mechanisms to encourage compliance with patient-reported outcomes. At UBC, we advance clinical research and patient recruitment from the perspective of these nine (9) categories: participants, motivations, messaging, targeting, delivery, setting, trust, privacy and leadership.

With each of these categories trending in a new direction, manufacturers will want to make sure they are updated on the latest developments to meet the demands of an evolving industry.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 2

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Participants: From Patients to VolunteersMany protocols are written to address existing or even retrospective evidence of medical need, which means that clinical trial participation is primarily focused on individuals with a recent, diagnosed health concern. However, as we look to the future, communication about and access to clinical trials will develop such that participation is a role that all people, regardless of health status, can fill. For example, there are presently registries and databases for the healthy off-spring of patients with Alzheimer’s disease that can be followed longitudinally for the potential of early intervention due to the possibility of developing the disease based on genetic risk factors. This also holds for currently healthy family members of patients with rare diseases and cancers, who may also have high-risk factors.

With this development, new opportunities exist to gather data from subjects who don’t fall into the typical methods of recruitment and research participation:

▶ Apple’s ResearchKit™ is just one tool allowing clinical research to reach the mainstream. Within a day of the March 2015 launch of ResearchKit™, thousands of volunteers signed up to participate in studies. The ResearchKit™ allows manufacturers and other researchers a means to take their studies out of a clinical setting and directly into participants’ hands. What may have taken a year in patient recruitment efforts could now take a matter of days.

▶ In his January 2015 State of the Union address, President Barack Obama announced the DNA Sequencing Project and called for federal funding for a national research program tracking the data of one million volunteer donors, including their DNA sequences.

Manufacturers will want to consider how to reach volunteer participants and the best study designs to optimize the vast amounts of genomic data they can provide.

Health technology and data analytics are at the heart of many programs that UBC supports. Sponsors are

partnering with UBC to conduct studies that provide insights into their product, as well as into provider and

patient behavior. As an Express Scripts company, UBC accesses a wide variety of proprietary data assets,

including both de-identified and PHI-containing platforms that provide real-time, real-world insights. In analyzing

billions of pharmacy and medical claims, we can understand late-breaking trends, target patient and providers

quickly and efficiently, and study the impacts of both specialty and traditional therapies in a longitudinal manner.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 3

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Motivations: From Incentives to AltruismWith this growth in volunteerism comes a demand for organizations, including sponsors, to promote high impact, meaningful experiences to keep volunteers engaged. While regulations greatly restrict payments and gifts to study subjects, sponsors still have an opportunity to tailor messaging and tokens of appreciation to recognize subjects’ contribution to research.

According to a poll by Research!America in 2013, of those participating in clinical trials, 86% cited the opportunity to improve the

health of others as an important factor in deciding to enroll.

The same poll shows that Americans are willing to share their personal health information — assuming that privacy protections are in place — so that researchers can better understand diseases and develop ways to prevent, treat and cure them (74%); so healthcare providers can improve patient care (72%); so public health officials can better track disease and disability (67%); and to advance medical research (73%).

Scientists, researchers, and patient recruitment specialists alike will want to be prepared

for more clinical research volunteers and more opportunities to gain valuable data specific

to multiple diagnoses and cancer types, especially for the healthy family members of

patients with debilitating diseases. UBC partners with sponsors to go beyond traditional

patient retention by creating online communities for study participants, providing study

results in lay terms, and even giving clinical trial participants their personal trial data.

UBC recognizes the importance

of a patient’s willingness to

share health information.

Upon enrollment into our

studies, we have the capability

to determine whether study

participants are enrolled as

members in Express Scripts’

pharmacy benefit management

(PBM) plan, and if they are,

obtain informed consent

to share that participant’s

relevant medical and pharmacy

claims. Appending medical and

pharmacy claims history to our

research studies adds depth

and efficiencies in the data

analysis process.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 4

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Messaging: From Broadcasting to Participative CommunicationsPatient communication with healthcare providers is rapidly changing in both style and substance. Patient portals have become a commonplace tool, allowing patients to schedule appointments, access lab results and diagnostic information, and communicate with their physician online. One-on-one communications with healthcare providers also is undergoing a marked change.

In a 2013 study published in the Patient Education and Counseling Journal3, researchers conducted an observational study to assess the different communication styles of physicians holding a consultative visit with their ailing patients who needed to make a decision about which cancer treatment plan was best for them. The study revealed four (4) predominant communication styles: broadcasting, directive, differential and participative.

The broadcasting communication style was the most widely used form of communication observed. This method is conducted as a monologue, lasting up to ten consecutive minutes without interruption, in which the physician provides information about the patient’s disease, prognostic information, and available treatment options.

Here are examples of other communication styles observed:

▶ Directive: Physician presents available treatment options, while incorporating advice or preferences, leading the patients to choose the approach the physician indicates is “best”

▶ Differential: Physician objectively explains all of the available treatment pathways and relinquishes the responsibility of selecting the treatment option entirely to the patient

And, while still not the leading form of patient-physicians communications, more and more healthcare providers are incorporating the participative style in which the physician begins an exam by asking questions and then pauses multiple times throughout the discussion to ensure comprehension. According to the study, patients engaged in participative communications were more likely to adhere to their treatment regimens and reported higher satisfaction with their physicians.

This evolution in communication styles can greatly affect clinical trial participation and sponsors will want to identify ways to adjust study protocols accordingly.

We understand the importance of a patient’s decision to participate in a trial

and the impact it has on both the individual and our sponsors’ ability to develop

medicines. UBC’s operations and patient recruitment experts set up a learning

environment that simulates interactions between the physician and the clinical

trial participant and offers coaching and practice scenarios to help our contracted

clinical research staff achieve a more participative communication approach.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 5

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Targeting: From Access to ValueIt’s no mystery that sponsors are increasingly tapping into the benefits of electronic medical records, hospital databases, pharmacy and medical claims, and even proprietary databases with patient data that can assist in both targeting and recruiting for clinical trial participation. While this massive aggregation of data is incredibly helpful as a starting point, barriers to using this data in the clinical trial setting can reduce its value.

First, the source of data is often not set up for the purposes of clinical trial recruitment. This means that the data is incomplete, providing only very small amounts of information that can help make decisions related to a specific protocol.

Secondly, the integrity of the data source can easily be compromised through aging records, lack of maintenance, and outdated information that reduces the number of records that are actually meaningful to a particular study.

Availability of the data, then, is a growing concern, as you factor in the appropriate consents and permissions needed in order to access the right information and reach out to potential participants. As well, the industry must adhere to federal regulations established to protect patient privacy, thus limiting how data may be accessed and used.

Working with our parent company, Express Scripts, UBC has the ability to link

targeted PBM members with relevant clinical research study opportunities, making

patient recruitment significantly more efficient. Analysts inside the PBM mine

data from more than 70 million patients who are eligible to receive mailers, phone

calls, and email invitations into clinical research studies. Sponsors should carefully

evaluate data sources based on the goals of a particular study.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 6

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Delivery: From Comprehensive to PersonalizedAll patients are not the same, and neither are their illnesses. Often described as providing “the right patient with the right drug at the right dose at the right time,” personalized medicine is changing the way drugs are developed and delivered to patients. Of the 51 new therapies approved by the Food and Drug Administration in 2014, 20 percent are considered to be personalized therapies by the Personalized Medicine Coalition4.

Personalized medicine typically uses diagnostic tools to identify specific biological markers, often molecular and genetic in nature, to help determine which medical treatments and procedures will be best for each patient.

Development of these treatments has a significant impact on how clinical studies are conducted. For these treatments, sponsors must identify sites that have a local lab or a lab partner that can perform genomic profiles. The time it may take for this specialized lab work should be built into the equation of these sophisticated studies.

Strong site support is important regardless of the therapy involved. What changes with these novel therapies is protocol and study design. More in-depth feasibility of practices will be needed before a study gets underway. Protocol development is also critical: Are the endpoints appropriate? Is correct data being captured? Sponsors should look for efficient ways to capture objective data to corroborate the physicians’ clinical assessments that can be gathered through solid tumor and hematologic response criteria.

In addition, sponsors will want to provide investigators the appropriate tools and resources to help patients participating in research with clear and specific instructions and support when reporting their health status. That support may include a dedicated contact center patients can call or it may include home health nurses. Strong patient support is especially critical to oncology studies.

Last year, UBC managed more than 50 oncology programs, working closely with physicians and their staff in

oncology networks, academic settings, and community-based healthcare practices. We understand the complexity

of personalized protocols and how to best support oncologists and their staff to be high-performing study sites.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 7

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Setting: From Fixed to FlexibleVolunteers report they would volunteer more often if the terms were shorter and more flexible5. Clinical trial participants also are looking for flexibility which is why UBC has seen a significant boost in our offering of home health nursing, concierge services and digital engagement tools to alleviate patient burden without affecting the integrity of clinical trial data.

Deploying home health nurses, who can take the trial to the patient, can help increase the number of patients available to participate in a trial and decrease delays in meeting enrollment goals. The convenience and care provided by home health nurses can increase compliance with study assessments — clinical and blood draws for labs — particularly for patients who are too sick to travel or those requiring a more flexible schedule. With the utilization of in-home services, studies have become more accessible and convenient, therefore more patient-centric. As well, the burden of the in-office visit is removed from the site, allowing more time to recruit patients and assure quality data is collected.

Nurses can also help patients have a full understanding of what is involved in participating in clinical research. Nurses can provide education, training, and additional support to both the patient and caregivers. Nurses may also act as a courier by picking up medication from a study site, transporting the product under proper coolant requirements, and ensuring the patient receives the therapy. By offering home clinical services, sponsors may experience faster enrollment, greater retention, and increased patient compliance.

Through telephonic support, nurses can play an important role in keeping patients engaged in clinical development and late stage studies. Like home health nurses, nurses staffing

a coordination center can provide patient education and therapeutic expertise, and even consent patients to study participation over the phone. While these nurses may never meet their patients in person, contact center nurses build trusting relationships and help patients overcome “trial fatigue” and remain on therapy.

Sponsors also are turning to technology to alleviate patient burden. Mobile technologies already are being used in clinical trial recruitment and retention, with the capacity to be used much more. Technology in clinical studies can include basic services, including text messages, scheduled visit reminders, mobile diaries to capture patient reporting, and access to online patient communities. In addition, technology can be used to provide patients with access to studies they would not otherwise know about and can offer personalized patient retention activities.

Technology also is in place that eliminates the need for some visits to healthcare providers, including smartphone-linked wearable sensors, point-of-need diagnostic devices, and medical-grade imaging at rapid speeds.

Industry projections estimate 6.1 billion smartphone users globally by the year 20206. With the increase in mobile device use, sponsors should consider the use of mobile health tactics early in study design. Does the protocol lend itself to mobile health technology? Can mobile technology be used to ensure continual patient engagement for retention and increased compliance?

Sponsors are now in a position to offer a number of options, including nurses and mobile technology that will help reduce patient burden and prevent burnout.

Through a network of home health

nurses, UBC has trained clinicians

within driving distance of more than

90% of the population of the

United States. We also support

patients with concierge services that

include transportation assistance.

On behalf of sponsors who want

to include digital technology in a

study, UBC provides quality market

research as well as pilot testing

capabilities. In addition, we work

with regulatory and technology

experts to integrate text messaging,

online chat functionalities, social

media and networking sites, as well

as online forums and blogs.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 8

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Trust: From Data to Evidence-Based DecisionsData is required to bring a drug to market, but real-world evidence is critical to building a long-term safety profile, maintaining market share, meeting payer expectations, and gaining patient loyalty. Prior to the Food and Drug Administration Amendments Act of 2007, post-marketing safety trials were voluntary. Many safety issues are not revealed until a drug is used by a broad population of patients outside the clinical trial setting. Post-marketing studies are important for monitoring potential side effects and understanding a drug’s impact on patients’ quality of life.

Increasingly, regulatory agencies, payers, prescribers, and patients are calling for sponsors to conduct studies that assess treatment decisions that can only be made with real-world evidence.

Whether conducting pre-approval or post-approval research, identifying, recruiting, and retaining the appropriate patients are

important. According to a study conducted in the United Kingdom in 20147, patients trusted their medical staff’s advice when:

▶ They received simple, clear answers and realistic advice

▶ They felt medical staff took the time to understand their concerns or questions

▶ The medical staff demonstrated an effort to work together and partner in the health goals and treatment plans

In short, the study found that trust is established through thoughtful and compassionate decision making, and through continued evidence of support throughout a patient’s journey.

Sponsors and research sites will want to include trial participants in creating workable protocols and including their input in protocol design and trial planning.

UBC is a market leader in designing and implementing post-

marketing studies. Our multidisciplinary teams of scientists and

global clinical operations experts are skilled in the design and

implementation of evidence-based approaches to real-world

data collection and analysis. In addition, our patient recruitment

experts have an important role in helping sponsors target the right

research participants. In partnering with Express Scripts PBM

analysts, UBC can identify target criteria and trigger outreach to

patients who may have interest in participating in clinical research.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 9

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Privacy: From Safety to SecurityClinical study sponsors spend a significant amount of time and money ensuring that patient data is collected and stored safely. In turn, volunteers participating in studies today receive a lot of information about how their data and health records are kept safe. Traditionally, this is accomplished through the use of paper or electronic data capture (EDC) systems, which typically are built to:

▶ Ensure compliance with regulatory norms

▶ Prevent unauthorized access to data

▶ Provide appropriate tools/module based on the role of the individual involved in clinical study

▶ Accommodate electronic signature and record

▶ Detect fraudulent data

Patients are informed of these safety and privacy measures during the time of consent to either provide their information or participate in a study.

“Data Safety,” while very important, has also placed limits on the value of information. When information is safe, it is stored and held in ways that are often exclusive to one particular purpose and isolated to a single event.

“Data Security” indicates that there is an expected and protected inflow and outflow of information.

For clinical trial participation to truly evolve and be more meaningful to the larger bodies of research taking place, we have to be able to build and utilize systems that are safe, but also secure.

So what allows for more security? The key is control. Systems are needed that allow participants to access their health records, learn outcomes of clinical studies and have some level of knowledge and control over where their information goes and how it is used.

Blue Button, an initiative of the U.S. Department of Health and Human Services, enables patients to access their own health data through technology. As a strong advocate for the Blue Button project, UBC encourages manufacturers to participate in this initiative. By providing study patients an easy way to access their clinical data once the study database is locked, patients’ interest and participation in clinical research is likely to increase. Furthermore, manufacturers demonstrate their primary commitment to patients by providing them with individual health data they can use and share with their providers, caregivers and others to integrate into their overall health management and treatment decisions.

UBC is working on a

first-of-its-kind project

that enables patients

who have participated

in clinical trials the

opportunity to download

their individual clinical

data, using Blue Button.

Through this project,

patients are empowered

to use their clinical

electronic data to

improve their overall

health and wellness.

UBC has launched its next generation, custom-built electronic data capture system

(EDC) which has been designed with safety of patients and integrity of data foremost

in mind. The system will collect and manage data for clinical trials, patient and

disease registries, and post-marketing programs. The system provides clients an

EDC solution that meets regulatory compliance while also being flexible and tailored

to fit the design and specific details of real-time management of research data.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 10

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Leadership: From Footprint to ImprintConsistent innovative business practice is going to be the driver of what makes an industry leader successful in the future. While mergers, acquisitions and collaborations are intuitively helpful in aggregating and pooling resources, the true leaders of the future will not primarily be based on size or number of resources. The future leaders in the clinical research industry will be those who consistently and habitually innovate, adapt and utilize the best in technological advances.

In studying some of the most innovative cultures, researchers show that true innovation tends to take place when resources are limited,

because it forces the innovators to prioritize, reduce waste, and only tackle the most pressing and impactful issues8.

Pixar Animation Studios is considered one of the most innovative companies of our current times, and they speak of their culture as one that fosters collective creativity. In this environment, “creativity involves a large number of people from different disciplines working effectively together to solve a great many problems.”

The life-sciences industry — and all patients — will benefit from this same culture of “collective creativity.”

Experts from across Express Scripts work

together in the Lab to find solutions for the

top challenges facing healthcare today. Our

goal is to create an environment of accelerated

test-and-learn innovation in partnership with key

thought leaders, clients and leading academic

advisors. Our work has earned us recognition

by Forbes as one of the World’s Most Innovative

Companies for the past two consecutive years.

Some of the work we do in the Lab includes

working with our proprietary data platform,

MediCUBE®. This data set allows us to

examine more than 130 million patient lives

longitudinally and in real-time, making clinical

research faster and more cost-efficient.

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved. 11

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

ConclusionBalancing the present needs in clinical research with the understanding of the implications and developments that are impacting our future is essential to improving healthcare. We can all start today by harnessing the enthusiasm of the growing number of volunteers participating in clinical trials, and messaging clinical programs with an emphasis on the rewarding and altruistic motivations our volunteers are experiencing.

We can continue to collaborate on finding flexible ways to reduce the burden of patient participation in clinical trials. We can view participants as unique, valuable, and informed. We can start the cycle of building trust by providing follow-up communications and demonstrating evidence of the value of clinical study participation. The ultimate goal for the future is to have participation in clinical research be culturally relevant, rewarding, and fulfilling with evidence of the impact that people are making in improving the health and lives of others.

About UBCUBC, a subsidiary of Express Scripts Holding Company, leads the market in providing integrated, comprehensive clinical, safety, and commercialization services. Working with Express Scripts’ specialty pharmacy and specialty distribution organizations, UBC is uniquely positioned to seamlessly integrate best-in-class services throughout the lifecycle of a product.

UBC brings together renowned scientific research and operations experts with leading-edge technologies, allowing for the best patient and healthcare provider experience.

Comprehensive, end-to-end services cover product and patient population characterization during development and market entry, as well as a focus on the patient experience, safety, and adherence.

Learn more about UBC’s services:www.ubc.com

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved.

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Sources Cited1. Jenkins, John M.D. “CDER Approved Many Innovative Drugs in 2014.” FDA Voice

(blogs.fda.gov). 14 Jan. 2014.

2. Zogby Analytics for Research!America. National Poll on Clinical Research. June 2013. http://www.researchamerica.org/sites/default/files/uploads/June2013clinicaltrials.pdf.

3. Chhabra, K.R., Pollak, K.I., Lee, S.J., Back, A.L., Goldman & Tulsky, J.A. “Physician communication styles in initial consultations for hematological cancer.” Patient Education and Counseling. 93(1), 573-578. Retrieved from: www.elsevier.com/locate/pateducou

4. PMC Analysis: More Than 20 Percent of FDA’s 2014 Novel New Drug Approvals are Personalized Medicines. 28 Jan. 2015. www.personalizedmedicinecoalition.org

5. Young, Matt J. & McChesney, Jon. “Contemporary Trends in Recreation Volunteerism.” Journal of Physical Education, Recreation & Dance. Vol. 84, Number 6. Aug. 2013.

6. Boxall, Andy. “The Number of Smartphone Users in the World Is Expected to Reach a Giant 6.1 Billion by 2020.” Digital Trends (www.digitaltrends.com) 3 June 2015.

7. Loon, MS., van Dijk-de Vries, A., van der Weijden, T., Elwyn, G., Widdershoven, GA. “Ethical issues in cardiovascular risk management: Patients need nurses’ support.” Nursing Ethics. 21(5). 19 Nov. 2013.

8. Catmull, E. “How Pixar fosters collective creativity.” Harvard Business Review. 86(9), 64-27. 2008.

N i n e E v o l u t i o n s i n C l i n i c a l R e s e a r c h & P a t i e n t R e c r u i t m e n t : A 2 0 1 6 P r e v i e w

Confidential & Proprietary | ©2015 Express Scripts Holding Company. All Rights Reserved.