Venkat Sethuraman, PhD

	On March 14, outgoing FDA commissioner Scott Gottlieb chided pharmaceutical companies and clinical research organizations (CROs) for being slow to embrace innovations in clinical research, even when the FDA sanctions those innovations. “The business model adopted by the clinical trial establishment just isn’t compatible with the kind of positive but disruptive changes that certain innovations can enable,” he wrote 

	The data back him up. Use of innovative designs such as 

 for Phase II and III trials. These innovations can increase the likelihood of launch for new drugs 

	Why, after 15 years, is pharma still struggling to adopt innovative trial designs? There remain many obstacles, including:

		  Lack of sufficient investigator, site, and patient input

		  Poor operational standardization of data and protocols

 of pharma’s approach to innovation among payers and patients 

	FDA keeps churning out guidelines for innovation 

	To foster innovation, the FDA recently offered a slew of initiatives. The agency’s 

 (September 2018) allows for the evaluation of multiple investigational drugs, disease types, or patient populations under a single clinical trial structure. (This is not new: the first “basket” trial, conducted by Novartis, tested imatinib mesylate in five different types of cancer in 

 (August 2018) promotes the use of seamless trial designs, Bayesian models and other advanced statistical approaches. And Gottlieb’s March 2019 press statement was a rollout for the FDA’s new guidelines on clinical trial 

-both practices key to precision medicine.

	However, guidance documents are not the whole story. For example, the FDA’s Master Protocol guidance suggests that sponsors use independent data monitoring committees (IDMCs) to conduct pre-specified and ad hoc assessments of endpoints and recommend protocol modifications. However, 

 has shown that there no standards for IDMC operating procedures, qualifications, and training.

	How can pharma address obstacles to innovation?

	Despite operational obstacles and low adoption rates, the industry has chalked up a few successes with innovative approaches. Effective strategies strike a balance between adopting innovation and mitigating risk. Companies can: 

		 Adopt clinical trial data standards and agreements proposed by organizations such as 

		 Provide patients with a virtual simulation of the clinical trial experience and offer logistics support to facilitate access to clinical trial sites

 that combine on- and off-site data to boost patient compliance and engagement in the process

, especially if the development plan involves using novel biomarkers, non-traditional clinical endpoints, or other innovations

	For its part, the FDA can continue to support innovation by sharing concrete examples of how sponsors and industry have worked together to solve problems and striving for better cross-divisional collaboration, standardization, and communication on crucial drug development issues. 

Venkat Sethuraman, Sharma Ramanathan Deva Devesa, 

Articles

FDA commissioner Scott Gottlieb criticized pharmaceutical companies and clinical research organizations for being slow to adapt innovations in clinical research, claiming that the business model adopted just isn’t compatible with the kind of changes that certain innovations can enable.

How Pharma Can Work with the FDA to Embrace Innovation and Overcome Its “Adoptaphobia”

	With nearly 80% of clinical trials failing to meet enrollment timelines, a better, more efficient approach to trial feasibility is critical. Fortunately, the availability of new analytics tools and an increase in data sources has led many companies to adopt a data-driven approach to decision-making during the feasibility process. Yet while this approach can have a massive impact on a trial’s success, oftentimes it’s not enough: Many companies’ efforts to utilize data in their decision-making are often manual, fragmented, and implemented inconsistently.

	How can companies develop and implement a data-and-analytics-driven approach to clinical trial feasibility and, ultimately, improve the success of their clinical trials? To help companies make evidence-based, end-to-end feasibility decisions, we’ve identified seven key building blocks for success: 

Understand the true patient and epidemiology landscape. 

Real-world data can be used for a variety of purposes in trying to identify the highest concentrations of patients. Epidemiology data can help companies develop heat maps and create a detailed picture of where eligible patients might be located, and which clinical sites and physicians are treating them. Real-world data can also be used to simulate medical events and symptoms to identify patients’ rare diseases. Social media data can be used to employ automated social listening techniques, supplementing RWD to identify eligible patients. You can use RWD to identify undiagnosed or underdiagnosed patients with diseases that physicians often struggle to identify. It can also be used to simulate medical events and symptoms to identify patients for rare diseases, which is an unmet need in the market.

Leverage competitive intelligence and landscape assessments. 

Understanding the competitive landscape is an essential step in the clinical trial feasibility process. A competitive intelligence assessment can help you choose investigators who have capacity or are participating in complementary rather than competitive trials. A competitive landscape assessment can help predict key metrics like the number of patients, sites, and investigators available for your trial, and the projected enrollment rates at a country and site level. A thorough understanding of a particular indication will help you create a plan for a trial that takes all other interventions, whether marketed or investigational, and their treatment guidelines into account.

Develop an effective enrollment forecast. 

Enrollment forecasting is an area where companies typically make critical errors. An aspirational enrollment timeline not supported by data can end up significantly impacting trial budgets. Start by looking at the availability of clinical trial patients based on eligibility criteria, and then mapping sites and investigator-to-patient ratios. Then, integrate all of this data to predict enrollment rates. Poisson-gamma and Monte Carlo are two commonly used methods for predicting enrollment curves. Accurate enrollment forecasting can also allow for accurate budget forecasting. Being able to complete these activities with precision can enable more efficient spending and better use of internal resources.

Identifying eligible patients using real-world data can help you determine which countries or regions are best for patient enrollment. Local clinical trial history can be derived either through open data sets, a company’s own internal data, or ideally a combination of the two. Data on average startup times or trial costs can help you decide where to conduct a particular trial based on your timelines and budget.  

Let data drive global site and investigator selection. 

In addition to external benchmarking data and internal data on historical site performance, companies also have data on site quality and investigator experience that can be factored into site selection decisions, such as average query resolution times, protocol deviations, etc. This data can be compared with historical benchmarks to get an understanding of how your company’s metrics compare to competitors.

A comprehensive understanding of the KOL landscape is an essential component of site selection, as having influential physicians spread out across a geography can drive referrals from the community to treatment centers. Beyond traditional KOL mapping techniques, you can utilize artificial intelligence and machine learning to identify influencers based on authorship of papers and practice guidelines, clinical trial participation, and editorial and leadership positions with journals and professional organizations.

Use global drug and asset profiles for your development strategy. 

Analyzing drug development data is important for head-to-head studies to know where comparable drugs are approved, how much they cost, what their approved label information is, and so on. Looking at competitive biosimilars, generics and branded agents’ approval status and market size should help inform a development strategy.

	Current methodologies for assessing trial feasibility won’t carry companies into the future. As our society continues to rely more heavily on data and digital solutions, companies that don’t implement data-driven decision-making will be left behind. On the other hand, clinical programs that leverage data science and analytics during the feasibility process will be positioned to find the right patients at the right sites and in the right regions. 

These seven key building blocks for success are outlined to help companies develop and implement a data-and-analytics-driven approach to clinical trial feasibility.

How Data and Analytics Can Improve Clinical Trial Feasibility

 and general good intentions, patient centricity is a concept that has eluded many in the pharmaceutical industry, especially in research and development. As some pharmaceutical companies strive and others hesitate to implement constructive strategies toward this goal, they’re discovering that study participants are no longer willing to remain passive bystanders in the quest for better health.

	Yet being patient centric in 2017 is much different than being patient centric 10 years ago. Today’s patients are more informed, engaged, and connected. For example, four out of five patients expect to be more active in managing their health than in the past.

 More than half of mobile phone users download health apps, and 65% of those users access their health apps daily.

 Likewise in Europe, one in five patients were more likely to go online to investigate their health decisions in 2016 than in 2014.

 This shift in how patients seek out and consume health information has far-reaching implications for drug development.

	Pharmaceutical companies also have to contend with an increasingly complex drug development and healthcare landscape, with a growing web of stakeholders influencing treatment approvals and health decisions. Scientists, regulators, industry payers, providers, and patients all are jockeying to have their voices heard across the development continuum, which historically was primarily focused on regulatory input.

	Meanwhile, trials are growing more specialized and complex, competing for ever-shrinking pools of eligible participants. A typical Phase III protocol has 86% more endpoints, 58% more procedures, 61% more eligibility criteria, and 58% more investigative sites than 10 years ago, 

 and finding patients for these trials is a continued challenge that makes headlines in the mainstream media.

	Patient centricity can play a role in helping to mediate some of the growing demands and complexities of trials. Truly patient-centric clinical trials enable sponsors to more directly and methodically align the objectives of a clinical trial to the true needs of patients and can result in more meaningful endpoints, an up-front understanding of operational issues, enhanced patient recruitment and patient retention, and better support for participating sites. But the strategies and skills necessary to design and execute successful, patient-centric clinical trials in this dynamic environment must keep pace with the changing landscape of empowered patients, drug development, and healthcare.

	Based on our extensive experience and original research conducted with clinical trial participants and pharmaceutical executives, we created a framework to address the evolving concept of patient-centric clinical trials. Described at length in an article by some of our colleagues,

 patient-centric drug development requires the following:

All sponsor stakeholders and trial administrators should understand the clinical trial patient journey and gain empathy for the patients’ and caregivers’ experiences.

Trials should measure outcomes that enhance patients’ lives while minimizing the burden on participants and their caregivers.

Pharmaceutical and medical device companies should provide trial participants with transparent, comprehensible trial information, data and results; support programs and resources through convenient and usable channels; and access to the growing potential of digital and mobile health technologies.

Sponsors should ensure that patient and caregiver engagement occurs throughout the trial by seeking input and feedback at every stage.

	These four pillars of patient centricity adapt to different phases of development, allow organizations to apply patient-centric strategic thinking to their trials, and provide guidelines to develop processes that would lead to a successful trial design or refine their efforts to move to the next level of patient centricity.

	For example, clinical trial patient journey mapping is an effective tactic to develop an initial understanding of the participant experience and can be a valuable tool to identify potential barriers to participation, trial pain points, and unmet participant needs before a trial begins. After surfacing these issues, organizations must engage patients and caregivers to co-create and test solutions that effectively address them. Inspired by design thinking, this “human-centered, prototype-driven process for innovation”

 is a valuable and flexible method for inspiring creative ideas and developing real solutions. By co-designing potential solutions with patients, and using simulations to test and refine those solutions, organizations can resolve would-be problems long before trials start.

	Patient centricity can help pharma organizations by striking a better balance between patient needs and desires and regulatory limits and requirements. Through a deeper understanding of and connection with patients, organizations can facilitate meaningful two-way communication to help manage patient expectations while being able to better meet their needs.

	For example, only 16% of oncology patients are aware that trials are a treatment option.

 With all of the recent advancements in medicine, the approval processes for new treatments can be lengthy. As a result, clinical trials could be a viable care pathway for many patients without available or effective approved treatment options.

 However, many oncology patients fear joining a trial and being randomized to the placebo arm, believing that this means they won’t receive treatment.

 While randomized trials are here to stay, new patient-centric communication and recruitment strategies are needed to increase patient awareness and ease anxiety as ethics require administration of the standard of care in the placebo arm for the majority of cancer trials.

	Patient engagement is necessary to identify patient concerns like these and to gain a deeper understanding of both the emotional and logistical barriers to trial participation. However, listing trials on clinicaltrials.gov or creating another patient communication explaining trial procedures isn’t enough: innovative, patient co-created solutions are imperative to addressing these pervasive gaps and doubts. Organizations should ensure that they have experts who understand best practices in patient-centric behavioral science and design thinking, and can apply these powerful tools in the context of clinical trials.

	At an organizational level, a commitment to patient centricity can help ease the challenges of balancing the needs of multiple internal and external stakeholders. By establishing a unified strategy and top-down approach to patient-centric thinking, organizations can achieve the company-wide mindset shift that’s necessary to becoming truly patient centric.

 Evidence demonstrates that strong leadership in this arena can pave the way to create necessary motivations and reward structures, remove common barriers and silos, and shape a cross-functional shift in company culture.

 Ultimately, this allows members at every level of the organization to more effectively help patients.

	Embracing patient centricity at the organizational level also allows companies to tackle another common challenge: measuring the ROI for patient-focused initiatives. A holistically patient-centric company will be empowered to evaluate the far-reaching effects of their efforts. By comparing “traditional” historical or competitor trials with more patient-centric trials, companies can expect to encounter fewer protocol amendments, shorter trial timelines, and fewer patient compliance issues.

	Time and again, sponsors have said that speaking to patients about potential trial protocols caused them to significantly alter the protocol and remove the perceived barriers to participation that the patients identified, ultimately saving the trial from costly and time-consuming protocol amendments.

 The impact of this across an organization could be substantial as over half of all protocols endure a major amendment, with the direct cost to implement such an amendment in a typical Phase III trial coming in at more than $535,000 per amendment.

	Talking to patients before a trial begins, or simulating the trial experience with patients, can also enhance participant compliance and satisfaction.

 Patients are quick to point out that procedures and tactics that are good to research designers are actually impractical or inconvenient to patients in real life. For example, providing ALS patients with activity trackers affixed with Velcro may seem simple and minimally disruptive, but these patients have expressed that such trackers are uncomfortable and damage their clothes, which invites frustration and noncompliance.

 Correcting problems like this before a trial begins-and capturing the potential impact-serves to increase the ROI for patient-centric companies.

	Externally, other stakeholders are becoming more focused on patient centricity, and pharma would be wise to keep up. Regulatory bodies have begun to offer guidance on patient engagement and encourage advocate involvement during development and evaluation. For example, the FDA has committed to patient-focused drug development and held more than 24 disease-area-focused patient input meetings between 2013 and 2017. Likewise, the European Medicines Agency revised its framework for interacting with patients in 2014, which gave rise to a marked increase in patient involvement. Sponsoring organizations that solicit similar patient input up front during the trial design phase will benefit from improved designs and be in a better position for regulatory discussions-a clear win for pharma, patients and regulators alike.

	Furthermore, regulators and even some payers are increasingly looking to pharma to demonstrate that new treatments

 provide real value that matters to patients; approval and even reimbursement decisions are more often influenced by patient-reported outcome (PRO) measures.

 Well-designed and properly executed PROs provide patients with the opportunity to engage in the data collection process and are key to capturing outcomes that patients care about. However, like any tool or tactic in a patient-centric trial, PROs must not be used haphazardly. Imposing numerous, irrelevant or poorly developed PROs on trial participants only increases their burden and may actually drive participants away. As a case in point, engaging the patient in the application of such instruments in a trial is imperative to ensuring that the information collected is relevant and meaningful to trials patients, and simulating their use in a trial is critical to assure that they don’t backfire and introduce an unacceptable burden.

	It’s critical that clinical trials continue to become more patient centric and adapt to ever-evolving patient needs. Some of the key considerations in achieving this include leveraging the methodological framework presented above and understanding trial patient needs and motivations, resulting in better trial design, recruitment and retention. By committing to patient centricity from the top down, applying the principles of patient-centric strategic thinking, and co-creating and simulating potential outcomes with patients, all trial stakeholders ultimately will benefit from better trials.

		Lisa Bance, PharmD, Associate Principal; Kristyn Feldman, PhD, Associate Consultant; Venkat Sethuraman, PhD, Associate Principal and Aaron Mitchell, Principal, all with ZS Associates. 

 Bryant, Adam. "Fix the Problem, and Not Just the Symptoms." 

			http://www.nytimes.com/2011/10/09/business/joseph-jimenez-of-novartis-on-finding-the-core-of-a-problem.html

			[2] “Self Care in Today's Changing Healthcare Environment.”

			http://www.bemedwise.org/documents/OHS_SC_Survey_FactSheet.pdf

			[3] Krebs, Paul, and Dustin T. Duncan. "Health App Use Among US Mobile Phone Owners: A National Survey." 

 3, no. 4 (2015). doi:10.2196/mhealth.4924.

			https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704953/

			[4] Key Patient Trends in Europe 2016.

http://www.drgdigital.com/infographics/infographic-eu-patient-digital-health-trends-2016

			[5] Getz, Kenneth. “Improving Protocol Design Feasibility to Drive Drug Development Economics and Performance.” 

International Journal of Environmental Research and Public Health

 11, no. 5 (2014): 5069-080. Doi:10.3390/ijerph110505069.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053871/

			[6] Kolata, Gina. “A Cancer Conundrum: Too Many Drug Trials, Too Few Patients.” 

https://www.nytimes.com/2017/08/12/health/cancer-drug-trials-encounter-a-problem-too-few-patients.html

 Mitchell, Aaron, Lisa Bance, Kristyn Feldman, and Nikita Reznik. “Pick Up the Pace on Patient Centricity in Drug Development.” ZS Associates. 2017.

			[8] Cohen, Reuven. "Design Thinking: A Unified Framework For Innovation." 

. April 4, 2014. https://www.forbes.com/sites/reuvencohen/2014/03/31/design-thinking-a-unified-framework-for-innovation/#216e3f178c11

			[9] Matczak, Jerry. "Patient Participation in Clinical Trials Infographic." LillyPad. Jan. 23, 2014. https://lillypad.lilly.com/entry.php?e=7073

			[10] "Phases of Clinical Trials." Cancer.net. Sept. 26, 2017.

			http://www.cancer.net/research-and-advocacy/clinical-trials/phases-clinical-trials

			[11] English, Rebecca A., Yeonwoo Lebovitz, and Robert B. Giffin. “Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary.” Washington, D.C.: National Academies Press, 2010. 64. https://www.ncbi.nlm.nih.gov/books/NBK50895/

			[12] Scutti, Susan. "Finding A Cure for Cancer Depends On Enrollment Of Clinical Trial Volunteers, Yet Fears Remain." 

			http://www.medicaldaily.com/cure-cancer-clinical-trial-387836

			[13] “‘Walking the talk’ in patient-centric pharma: What it will take to make a radically new business model work.” Heidrick & Struggles International, Inc. 2014.

			http://knowledge.senndelaney.com/docs/thought_papers/pdf/Heidrick_SennDelaney_patientcentric.pdf

ZS Associates specify the four pillars of patient centricity that can help the demands and complexities of clinical trials.

Venkat Sethuraman, PhD

Articles

How Pharma Can Work with the FDA to Embrace Innovation and Overcome Its “Adoptaphobia”

How Data and Analytics Can Improve Clinical Trial Feasibility

Four Pillars to Achieve Patient Centricity