New R & D Patient-Centric Models

The traditional drug development model follows a linear path, from discovery to the preclinical stage, leading to phase I, II, and III human trials to support approval by the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other regulators. A new model is emerging, involving patients as co-creators at each stage. Analytics allow a more predictive approach, often including biomarkers and companion diagnostics. Innovation itself is now more open, thanks to crowdsourcing technologies. Trials are optimized with e-recruitment and e-reporting. The supply chain is also enabled by real-time insight for forecasting, patient input for product formulation, and innovative cloud-based worldwide distribution.

As post-market data collection continues to blur the lines between research and commercial outreach, R & D supports marketing activities through an evidence-based communications strategy. The impact of digital technology on the value chain is summarized in Figure 9-1. In research, scientists can discover new care pathways by mining genetic and clinical data. In clinical care, big data may fuel a new paradigm for epidemiology by combining environmental data with user queries on search engines such as Google.

Online patient communities can also help find and recruit patients with rare diseases, but challenges remain for wider adoption of digital technologies in R & D. Electronic health records (EHRs) offer significant opportunities to optimize treatments on a broad scale, but they are still fragmented and may have large biases; for instance, they may exclude the populations served by understaffed hospitals without the necessary infrastructure [1]. In epidemiology, a new approach was pioneered in 2009 by Google as it published its Flu Trends initiative [2]. However, a subsequent paper reported that, for 2013, Google showed almost twice as many flu cases as were estimated by the Centers for Disease Control and Prevention (CDC) [3].

Optimizing Clinical Trials

Digital technology can transform several stages, including recruitment, remote monitoring, and post-marketing surveillance. According to the Institute of Medicine, 75 percent of US trials fail to enroll their target numbers, and 90 percent do not reach that target within the specified time [4]. In addition to databases such as ClinicalTrials.gov, patients can now find trials through Google and Facebook ads, as well as online communities. For instance, Biogen has partnered with PatientsLikeMe and Fitbit to better understand the utility of wearables for tracking activity in multiple sclerosis patients and also to explore patient adherence to monitoring after the study. Apple's ResearchKit is used by many health systems, including Mount Sinai for their Asthma Health app; more than 8,000 participants enrolled in a clinical study within six months, and only 13 percent of them were located near the New York study site [5].

During trials, mobile devices allow real-time patient feedback, reducing in-person visits and giving an objective measurement of therapy response. Early signals of efficacy and safety can also help identify patient subsets with better responses and allow trial restructuring. Postlaunch, real-world evidence helps monitor efficacy and adverse events that may not have appeared within the limited scope of trials. For instance, Pfizer and IBM have launched a research project on Parkinson's disease, using sensors to provide real-time symptom information and medication timing and dosing, thus defining the digital signatures of individual patients. The study targets up to 200 participants including controls, and aims to discover which sensors can best provide correct insights and speed up trials. By 2019, Pfizer may apply this method to a phase III trial of a new compound and later extend it to other degenerative diseases such as Huntington's and Alzheimer's [6].

Role of Social Media in Trials

Patients are taking a direct role in trials. As noted in Chapter 6, PatientsLikeMe was launched in 2004 with a focus on amyotrophic lateral sclerosis (ALS) and has since expanded to more than 2,700 conditions, with over 500,000 members. In 2013, it launched its Open Research Exchange, funded by a grant from the Robert Wood Johnson Foundation to link scientists and members, who can log patient-reported outcomes (PROs) on it. This was expanded in 2015 with a $900,000 Robert Wood Johnson Foundation grant to fund a collaboration with the National Quality Forum, aiming to develop and test the broader use of PROs [7]. In 2016, PatientsLikeMe and informatics firm M2Gen started combining PROs with molecular and clinical data from patients in the Total Cancer Care Program at Ohio State University, with a focus on lung cancer. The alliance is funded by PatientsLikeMe partners AstraZeneca and Genentech [8].

Other patient communities have successfully funded trials in rare diseases and enabled rapid enrollment in such trials through their patient network. By the mid-2000s, the Leukemia and Lymphoma Foundation was deploying about $50 million annually to fund 350 research projects worldwide. In 2013–2014, pharmas contributed at least $600 million to further development for blood cancers [9]. Biopharmas are increasingly engaging in long-term collaborations to optimize research, not only with patient communities but also with infotech leaders.

While social media are helping optimize trials, some mixed reports are emerging. Apps developed for Apple's ResearchKit by health systems such as Mount Sinai (asthma) and Massachusetts General Hospital (diabetes) have enabled broader and faster enrollments (more than 70,000 participants in the first two months) [11]. However, active conversations within patient communities during trials may undermine data integrity in areas such as eligibility (patient coaching about how to meet criteria), blinding (advice on how to get into a therapy and not a control arm), and safety (sharing adverse events may trigger a false spike in safety reports) [12]. To mitigate these risks, sponsors may take into account the activity intensiveness of various communities, the study size (one e-participant may influence a small study to a larger degree), and possibly complement the e-consent process with patient education about these risks.

Wearables: Growth and Challenges

In parallel with biopharma initiatives, market demand has driven two related trends: wearables (sensors worn on the body or in clothing to track activity and vital signs) and their link to social media. While wearables have shown exponential growth, company success has been uneven, in part because consumers are generally more satisfied with hardware (devices such as the Fitbit wristband) than software (fitness and health apps). According to BCC Research, mHealth, defined as “medical and public health practice supported by devices such as mobile phones, patient monitoring services and other wireless devices” [27], is expected to reach a global revenue of $21.5 billion by 2018, with Europe as the largest mHealth market [28].

Smartphones themselves, however, are showing signs of saturation. IDC (International Data Corporation) reported a flattening of global shipments, as Apple showed a first-ever decline in 2016 and Samsung (the largest maker of Android phones) also saw a fall in sales. As nearly 80 percent of Americans own smartphones, the market may be driven only by upgrades and conversion of the remaining nonusers [29].

A parallel trend is the proliferation of apps but a low level of satisfaction. Of the 165,000 health-related apps on Apple's iOS and Google's Android, most are rarely used and many are quickly abandoned. According to a 2015 IMS study, more than 50 percent of health apps have narrow functionality (often just information, without interpretation). Only 2 percent of apps have connectivity with provider systems.

Multiple barriers persist, including lack of integration between EHR systems, regulatory uncertainties, and privacy concerns. For physicians, the lack of infrastructure to handle massive patient inflows is compounded by liability and reimbursement issues.

Because of its fragmented healthcare system, the United States lags Europe. Denmark leads in mHealth utilization, level of digitization, and regulatory framework. In 2015, the National Health Service (NHS) in England launched a website and related app to treat depression and anxiety, and improve access to mental health services [30]. Some progress is being made in the United States, as the Mayo Clinic, Geisinger Health, Kaiser Permanente, Intermountain Healthcare, and Group Health formed, in 2015, the Care Connectivity Consortium to share patient data in a secure exchange.

A growing body of evidence is also being collected through collaborations. The Dana-Farber Cancer Institute and Fitbit announced, in April 2016, a partnered study of the impact of weight loss on cancer recurrence, sponsored by the National Cancer Institute and the Alliance for Clinical Trials in Oncology. The study aims to enroll more than 3,200 overweight women with early-stage breast cancer, to be randomized for a two-year weight loss and education program, versus health education alone. Fitbit is donating a fitness and heart rate tracker, smart scale, and software for video exercises on mobile devices [31]. It remains to be seen within what time frame the current vertical solutions can evolve from consumer-grade devices and apps to FDA-approved research-grade devices with curation of apps, provider buy-in, and interoperability across the care continuum, from patients to physicians and health systems.

Consumer concerns are also exacerbated by massive data breaches such as those of Anthem and Premera Blue Cross. Anthem alone suffered a breach of 78.8 million records in early 2015. Security experts agree that healthcare data has a much longer value than credit card information, as theft and misuse take a long time to show up in fraudulent billing and medical records [33]. Consumers are therefore reluctant to share data digitally. A 2013 Health Information National Trends survey of more than 3,000 patients showed that only 6 percent had actually shared health data through their devices, and that less than a quarter would be willing to do so for digital images or diagnostic information [34].

Some privacy risks may not even be publicly known. The Journal of the American Medical Association reported in 2016 a study of 211 Android diabetes apps that showed that 81 percent did not have privacy policies. Permissions (which users must accept to download an app) authorized collection and sharing with third parties of sensitive information such as insulin and blood glucose levels. There are no federal protections, including within HIPAA (the Health Insurance Portability and Accountability Act) against the sale or disclosure of data from apps to third parties [35].

The FDA has released several guidelines, including a 2015 guidance on electronic consent in trials, requiring clear information and ease of navigation [36]. It has stated its intent to calibrate regulation, overseeing only mobile apps and devices that could pose a safety risk if they malfunction, such as electrocardiography devices like AliveCor [37]. In its capacity to regulate false and deceptive advertising, the Federal Trade Commission (FTC) has already brought enforcement proceedings against two app developers, including one claiming to treat acne through light from a mobile phone. In addition, the Department of Health and Human Services (HHS) monitors HIPAA violations, and in July 2013 it fined WellPoint $1.7 million for failing to provide adequate safeguards for its online app database [38]. This conflicting pattern of rapid, mostly uncontrolled growth and related risks also applies to the evolution of social media in healthcare.

Social Media: From Insight Mining to Co-Creating

According to the Pew Research Center, 65 percent of American adults use social media, up from 7 percent in 2005, but the overall number of users has leveled off since 2013. While 90 percent of young adults use these sites, as many as 35 percent of those over 65 also do [39].

In its 2015 Cybercitizen Health US study, Decision Resources surveyed 6,601 US adults and found an overall demand for disease-oriented information, rather than drug data. Up to 38 percent of respondents had searched symptoms and conditions in the past 12 months, and up to 39 percent had done so through search engines versus 18 percent on social networks, only 12 percent on prescription drug websites, and even fewer (8 percent) on pharma corporate sites. The top site used was Facebook, closely followed by WebMD, with Twitter far behind. The top types of information sought were factual: prescription drugs' efficacy and side effects, followed by news feeds and provider ratings [40].

The use of private online physician ratings has greatly increased, with 8.9 million unique visitors for Healthgrades in September 2015 alone, partly because public websites such as Physician Compare include overly complex data or measures of clinical quality not meaningful to consumers, who are more interested in service components than mortality statistics [41].

In addition to provider ratings, the dominant need for disease information explains the growth of patient communities. Among others, PatientsLikeMe allows members to track their disease status and compare it with de-identified data from a large database, and to access customized clinical trial information. This trend is worldwide: in Europe, RareConnect is a site from EURORDIS (European Organization for Rare Diseases), with financing from public funds, events such as telethons, and corporate sources. PatientsLikeMe has partnered with the FDA to improve the reporting of adverse effects and has developed measurement tools through its Open Research Exchange. Given that 30 to 55 percent of patients with hypertension do not adhere to their medication regimen, PatientsLikeMe codeveloped with the Villanova College of Nursing a management instrument that would be free to physicians and would be completed during office visits to add PROs to clinical data [42].

The most advanced strategies belong to rare diseases, where some groups have actually funded trials and codeveloped breakthrough treatments. After its first investment in Aurora (later Vertex), leading to the 2012 FDA approval of Kalydeco (ivacaftor) for patients with a rare gene mutation, the Cystic Fibrosis Foundation is now funding research programs with Pfizer, Sanofi/Genzyme, and Shire. It has invested $425 million as part of its venture philanthropy model, and, in 2014, it sold its royalty rights for cystic fibrosis treatments developed with Vertex for $3.3 billion, to further develop new therapies and to provide online support of patients [43].

Given this rapid patient empowerment through social media, but also regulatory constraints, it would be prudent for biopharmas to adopt a stepwise approach. An indispensable first step is a sophisticated listening function, tracking what consumers are seeking online, but also what they are saying between themselves on social media. Beyond insights mining, companies can then reflect and shape the consumer demand for disease information with an unbranded portfolio ranging from blogs to compendia such as the Merck Manual. Some companies are issuing corporate posts on topics such as patient access information. Although practiced by a few biopharmas, branded messages remain a risk on uncontrolled social media. Facebook continues to allow pharma brands to disable comments, so many of the existing branded pages offer only the ability to share content but not respond [44]. These steps reflecting different degrees of risk are summarized in Figure 9-4.

Best practices for biopharmas could also include the following steps:

• Listen: What conversations are happening around your disease and product?
• Audit: What are consumers' preferred platforms? Do they correspond to those you already use?
• Create content: Develop content that addresses patient pain points and their entire journey, including the pretreatment and posttreatment stages.
• Integrate: Pilot new initiatives and integrate them into overall social publishing
• Coordinate: Coordinate a consistent message across functions, from R & D to health economics and market access, customer relations, sales, and marketing.

In addition to extensive involvement with consumer trends and behaviors, eHealth success for biopharmas also depends on an understanding of provider-centered initiatives including telemedicine.

Physician Digital Trends

While biopharmas aim to increase their patient and physician engagement, studies show a clear physician preference for other information sources. A 2015 Decision Resources study of 3,029 US practicing physicians showed that their clinical decisions are mostly influenced by conferences, colleagues, and journals, while pharma representatives were cited by less than a third of respondents. The professional apps most used were Epocrates, UpToDate, and Medscape, with their main attractiveness being quick access to information and ease of navigation. For online videos watched for clinical purposes, the same trend applied, with Medscape Professional Network and YouTube cited first versus only 8 percent using pharma websites. These videos were primarily for continuing medical education, seminars, medical procedures, and disease information [47].

Scope of Digital Services

Beyond these clear physician trends, the healthcare landscape is being fundamentally changed by a broad range of new and existing players, from on-demand services to device manufacturers (Figure 9-5). Several competitive threats are emerging for providers as well as biopharmas, as patients are partly migrating to on-demand services, content portals, and even pharmacy chains. These entities act to disintermediate communications between biopharmas and patients. For example, online portals like WebMD and Everyday Health are transitioning from content to service providers. WebMD offers a private wellness portal to self-insured employers and health plans. Its partnership with Walgreens integrates its content into the retailer's experience to track and reward healthy behavior. Everyday Health partners with Cigna for early risk identification in prenatal care, and it has also an alliance with the Mayo Clinic [48].

On-demand services represent a “convenience revolution,” as they provide real-time consultations at about half the cost of standard visits. Players include MDLive, Doctor on Demand and American Well, and some firms such as AmeriDoc also offer lab testing services. Although some sites claim that they are reviewed by internal medical boards, most do not offer external validation or continuity of care.

A study published in May 2016 by JAMA Dermatology surveyed 16 online telemedicine companies, including seven general sites and nine focused on dermatology. Researchers created six fictitious scenarios and used stock images. Some sites misdiagnosed syphilis, herpes, and skin cancer, and two linked users to overseas doctors not licensed to practice where patients were located. Of the 14 clinicians who viewed photos of nodular melanoma, 11 correctly told the patient to see a doctor, but 3 diagnosed it as benign. According to the American Telemedicine Association (ATA), these services have grown rapidly, with more than one million e-visits expected in 2016. Many insurers cover them, generally for costs between $35 to $95. Given quality concerns, the ATA began an accreditation program in 2015. Although nearly 500 telemedicine companies applied, only 7 had been approved as of May 2016 [49].

Faced with competition from new insurers such as Oscar Health, health plans have also developed online services. UnitedHealthcare has 16 telehealth partners and remotely monitors 20,000 members in their homes. Anthem also launched, in partnership with American Well, its LiveHealth program to be rolled out to its 33 million members, as a 24/7 service costing $49 per visit. These payer initiatives aim, in part, to minimize misuse of emergency rooms by patients with non-urgent issues.

Top therapeutic areas for telemedicine include mental health, dermatology, and cardiology through synchronous services (real-time consultations) and asynchronous services such as the transmission of radiology images.

Reimbursement from Medicare is slowly improving. Although there is no federal mandate, states have the option to reimburse for Medicaid teleservices, and many, including California, New York, and Pennsylvania, already cover videoconferencing. In addition, 21 states and the District of Columbia require private payer reimbursement, at varying cost levels [50].

Effectiveness of Telemedicine

Key issues for telemedicine remain its accuracy and cost effectiveness, which have been best analyzed by health systems. The Veterans Health Administration (VA) has a large program collecting data from over 17,000 participants, for illnesses ranging from diabetes to depression. It demonstrated high patient satisfaction, a 25 percent reduction in bed days, and a 19 percent reduction in hospital admission when compared with usual care.

Partners Healthcare conducted a randomized trial using a wireless pill bottle, together with feedback services and reminders for hypertension patients. Initial findings showed a 68 percent higher rate of medication adherence, compared with controls [51]. Similarly, in its Hospital at Home model, Johns Hopkins achieved comparable outcomes versus inpatients and yielded overall cost savings of 19 percent, generated, in part, from lower average length of stay and fewer diagnostic tests [52].

European initiatives have also generated positive results. In the United Kingdom, the Department of Health Whole System Demonstrator program, launched as early as 2008, was a 12-month study of 3,230 patients with diabetes, chronic obstructive pulmonary disease, or heart failure. Intervention participants, receiving telehealth equipment and monitoring services, showed fewer hospital admissions and lower mortality, also with lower costs per head.

In the United States, remaining barriers include licensure, privacy concerns, and broadband access, as some rural locations lack adequate network infrastructure. Only about 10 state medical boards issue licenses allowing interstate telehealth, but portability is expected to increase. A longer-lasting barrier may be liability fears. Teladoc and American Well both cover the cost of malpractice insurance, but risks persist if patients use telemedicine alone instead of as a complement to in-person visits [53]. Finally, interoperability remains a challenge, even though some EHRs have started exchange programs.