	It’s an old chestnut: does a cozy, cash-based arrangement between the investigator and the drug’s manufacturer produce positive clinical trial results? “Yes” is the clear answer, according to a new study by researchers at University of California San Francisco (UCSF).

	Financial links between researchers and companies that make the drugs they are studying are independently associated with positive trial results, suggesting bias in the evidence base, concludes the study, published online by 

	Salomeh Keyhani, MD, associate professor of general internal medicine at UCSF, and her colleagues evaluated the association between financial ties of principal investigators (PIs) and study outcomes in a random sample of 195 drug trials published in 2013. They focused on trials that examined the effectiveness of drugs.

	 The group, lead author of which was medical student Rosa Ahn, found that financial ties between principal investigators and the pharmaceutical industry were present in 132 (67.7%) studies. Of the 397 PIs, 231 (58%) had financial ties. Of all PIs, 156 (39%) reported advisor/consultancy payments, 81 (20%) reported speakers’ fees, 81 (20%) reported unspecified financial ties, 52 (13%) reported honorariums, 52 (13%) reported employee relationships, 52 (13%) reported travel fees, 41 (10%) reported stock ownership, and 20 (5%) reported having a patent related to the study drug. The prevalence of financial ties of PIs was 76% (103/136) among positive studies and 49% (29/59) among negative studies.

	Trials authored by PIs with financial ties to drug manufacturers were more likely than other trials to report favorable results, even after control for confounders such as funding source and sample size (odds ratio 3.37, 95% confidence interval 1.43 to 7.9). Ahn and Keyhani point to possible mechanisms linking industry funding, financial ties, and trial results such as bias by selective outcome reporting, lack of publication, and inappropriate analyses.

	An unexpected finding was the lack of association between industry funding and favorable trial results in multivariate analysis, noted Andreas Lundh, PhD, a post-doc researcher at the Center for Evidence-based Medicine, Odense University Hospital and University of Southern Denmark, in a 

 linked editorial. Interpretation of this finding is complicated, however, because Ahn’s study used a definition of industry funding that grouped company-run trials with independent academic studies that also received industry funding, he pointed out.

	Also, financial ties are often unreported, and although Ahn and colleagues did make efforts to identify undisclosed financial ties, the databases available for such purposes are still limited, Lundh wrote.

	Ahn, Keyhani, and colleagues stress that their analysis is observational and cannot be used to draw conclusions about causation, but given the importance of industry and academic collaboration in advancing the development of new treatments, they think “more thought needs to be given to the roles that investigators, policymakers, and journal editors can play in ensuring the credibility of the evidence base.”

	 Lundh and co-author Prof. Lisa Bero, from the Charles Perkins Centre and Faculty of Pharmacy, University of Sydney, Australia, agrees more research is needed to identify how industry funding and financial ties could influence trial results. They urge trial authors to share their data and participate in industry-funded studies only if data are made publicly available, and they suggest journals could help by rejecting research by authors who are unwilling to share their data and by penalizing authors who fail to disclose financial ties. The role of sponsors, or companies with which authors have ties, in the research must also be transparent, they stated.

	 “Trials with industry funding or authors with financial ties should be interpreted with caution until all relevant information is fully disclosed and easily accessible,” they concluded.

Articles

News

Study finds that financial links between researchers and drug manufacturers are independently associated with positive trial results.

Investigators’ Financial Ties Come Under Close Scrutiny

	It’s not just science that is leaping ahead and taking clinical trials into new territory. The world is changing around science, and one of the consequences is that there are changes, too, in the ethical context for medicine. What was until recently considered ethically sound is now no longer so adequate-and that is why, in February, the Council for International Organizations of Medical Sciences (CIOMS) is publishing its final version of its revision of one of the texts underlying all modern trial protocols, its 2002 International Ethical Guidelines for Health-related Research Involving Humans. 

	This 120-page document will have to become the new bible for everyone working in clinical trials, observational research, biobanking, and epidemiological studies. Its chapters cover virtually every aspect of trial design and conduct, from informed consent to compensation for research participants, and from ethics committees to cluster randomized trials. Almost all guidelines are newly drafted, and major revisions have been introduced to guidance on risks and benefits, choice of control, and women. Its scope has been expanded from “biomedical research” to cover all health-related research, and it has been merged with CIOMS’ 2009 International Ethical Guidelines for Epidemiological Studies. 

	Most notably, the document brings a new emphasis to what can best be described as the general good, in line with the development of more socially aware public discourse on health over the last two decades. There are now extensive guidelines on scientific and social value and respect for rights, on equitable distribution of benefits, on community engagement, on public accountability, and on conflicts of interest. CIOMS decided on an update because of developments since 2002, both in the field of biomedical research itself and in research ethics-including, notably, the revision of the Declaration of Helsinki in 2008. 

	So a new provision, right up at the front of the guidelines, is that “the ethical justification for undertaking health-related research involving humans is its scientific and social value.” To be ethically permissible, health-related research with humans, including research with samples of human tissue or data, must have social value, CIOMS insists. It explicitly outlaws “seeding trials” if their purpose is to influence participating clinicians to prescribe a new medication rather than to produce knowledge about the merits of these interventions. Similarly, even a well-designed, late-phase clinical trial could lack social value if the endpoints measured are not sufficiently related to clinical decision making.

	Keeping research relevant also gets new attention in these guidelines. “Before instituting a plan to undertake research in a population or community in low-resource settings, the sponsor, researchers, and relevant public health authority must ensure that the research is responsive to the health needs or priorities of the communities or populations where the research will be conducted,” says CIOMS. And benefits must be shared: "Sponsors, researchers, governmental authorities, and research ethics committees and other stakeholders must ensure that the benefits and burdens of research are equitably distributed,” the guidelines demand. So trial participants must be selected "for scientific reasons and not because they are easy to recruit given their compromised social or economic position or their ease of manipulability."

	The rise of patient power is also reflected in the new guidelines. "Researchers, sponsors, health authorities and relevant institutions should engage potential participants and communities in a meaningful participatory process that involves them in an early and sustained manner in the design, development, implementation, informed consent process and monitoring of research, and in the dissemination of its results," according to CIOMS. This is a matter of showing respect for communities and for their traditions and norms, but it is also "valuable for the contribution it can make to the successful conduct of socially valuable research."

	This injunction is not merely a form of words. The guidelines lay down what it means in practice. The research protocol should include a description of the plan for continued community engagement, and identify the resources allocated for this, with a list of what has been and will be done, and by whom, to ensure that the community is clearly defined and can be engaged to ensure that the research is relevant and accepted.

	Women, and particularly pregnant and lactating women, benefit from additional attention in the new guidelines. Because they have distinctive physiologies and health needs, research designed to obtain knowledge relevant to their health needs must be promoted, says CIOMS, adding that research in pregnant women must be initiated only after careful consideration of the best available relevant data. In any research interventions or procedures that have no potential individual benefits for pregnant and breastfeeding women, the risks must be minimized, and the purpose of the research must be to obtain knowledge relevant to their particular health needs or those of their fetuses or infants.

	The rise in privacy concerns over recent years also informs new guidelines on biological materials and related data. In addition to provisions on governance for collection and storage of everything from tissue specimens to health records, CIOMS requires that when specimens are collected for research, either specific informed consent for a particular use or broad informed consent for unspecified future use must be obtained from the person from whom the material was originally obtained.

	The guidelines demonstrate, however, a pragmatic approach to use of any residual tissue. Where this is stored for future research, a specific or broad informed consent may be used, or may be substituted by an informed opt-out procedure. And when researchers seek to use stored materials collected for past research or clinical purposes without having obtained informed consent for their future use for research, a research ethics committee may waive the requirement of individual informed consent if the research would not be feasible or practicable to carry out without the waiver and has important social value.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium

Europe is issuing a significant update to its ethical guidelines governing health-related research involving humans.

Times Changing for Ethics Guidelines, too

 spoke with Christine Hurley, chief operating officer for 4G Clinical, a new entrant into the randomization and trial supply management (RTSM) space, about making the transition from the industry sponsor side, where she was most recently associate director of clinical systems and technology with Biogen Idec, to the supplier business. She also discusses the evolution and challenges of technology innovation and its implementation across the drug development enterprise.      

It’s been over a year since you left the sponsor side for the vendor side. What is the most important thing you have learned-from either viewpoint-that you didn’t know before?

	That there is no single best technology solution, or strategy, for every company.  What does that mean? While it might be considered an emerging best practice to use a particular type of technology to support a certain business process. For example, buying and implementing a centralized temperature deviation database to manage cold chain excursions. It isn’t necessarily right

 for every organization to buy one at this moment to meet their business goals.  In fact, it can have the opposite effect and be so disruptive to the business that it backfires and turns companies off to innovation.  

	When technology implementation fails, it is often perceived as a fault of the system itself, when it is more often a change management failure. I am a huge proponent of applying technology wherever you can, but it is essential that an organization develop a technology strategy that enables their business goals and prioritizes technology implementation carefully. It is crucial that technology vendors understand their clients’ business and technology strategies and how their particular software fits into that strategy so they can best partner to help their clients succeed.

Q: When it comes to innovation, many seem ambivalent that it equates to real change or improvement. When do you know that an innovation is truly impactful? How is that measured? 

	I do think there is some weariness in industry about the term “innovation.” I’ve heard many comments along the lines of “oh, everyone says their system is innovative or they are innovating”-what does that even mean? Impactful innovation in our industry at the highest level, to me, means directly improving the lives of patients.  How do you measure that? Does your software significantly shrink timelines and speed up a business process? Does your software improve the quality of data collected, which then, in turn, speeds up data cleaning and analysis? When clinical professionals are in the critical stage of starting up a clinical trial, have we simplified things for them? Have we removed steps in the start-up process?  Have we made something simple that used to be feared-or simply wasn’t understood?  The measure is a challenge for sure; if you can tie improvements to faster start-up timelines, you have a metric that everyone will relate to.

Q: It’s well discussed that the pharma industry does not quickly embrace change. How can people get more accepting of technological change in clinical trials?

	What immediately comes to mind is how crucial it is that technology is built on a deep understanding of the business process it is enabling. When offering technical solutions in the clinical space where your customers are clinical experts, not software development experts, it is paramount that the software support their processes. In order to provide a compelling argument that the technology will improve their process/jobs/ time-to-patient impact, you have to demonstrate that you understand their processes and the challenges of their jobs.

	This might sound simple but too often in this industry we see biotech and pharma organizations working their process around the system that they have and, inevitably, it doesn’t work as expected, or worse, there are quality issues. In an industry as regulated as ours, successful technology change must start with business expertise.

Q: There are clinical trial processes or areas that are ripe for technology innovation, which is how your company launched in the RTSM area. Do you see other processes that could be positively changed with new approaches?

	Absolutely. As you’ve said, our industry has a reputation for being slow to change, especially in the technology area, and certainly there are opportunities across all aspects of clinical development that we could consider automating or improving. A few trends/areas that I’ve been especially interested in this year relate to clinical sites. I’ve been fortunate enough this year to work directly with clinical sites to get their input into our RTSM product, and I can’t stress how valuable that feedback is. Clinical sites, with tens of trials running at a time using multiple systems for each-all doing different things-layer onto that site processes that all must be followed independent of sponsor requirements.  

	After many years in the industry, it was truly eye-opening for me. One investigator, with about 30 years of experience, noted they had never been asked by a sponsor for feedback about the tools that they use. I think site engagement and communication related to clinical technology-both at start up and ongoing-is an area of deep possibility. 

Editor’s note: Watch Christine Hurley discuss advances in clinical trial supply management on the ACT TV player on our 

Q&A explores the evolution and challenges of new technology implementation in clinical trials.

Disruptive Innovation and the Technology Strategies Needed

	Congress surprised policymakers and the research community in December by enacting the 21st Century Cures bill after two years of debate. Final enactment was secured by adding language to fund state opioid treatment programs, expand mental health services, and promote research on regenerative medicine. 

	The new law shores up FDA operations and funds biomedical research at the National Institutes of Health (NIH), including the Obama administration’s Cancer

 Moonshot and personalized medicine initiative. Key provisions support patient-focused drug development, pediatric research, biomarker qualification, and the development of needed antibiotics and treatments for rare conditions. Most important for FDA officials are policies designed to help the agency hire more scientists and experts to evaluate new products and research programs.

	A theme is to encourage researchers to apply novel adaptive designs and statistical modeling to clinical trials and to permit wider use of real-world evidence in approving added indications for marketed medicines. Medical device makers gained a new approval pathway for “breakthrough” devices, and there’s language reducing diverse conflict-of-interest reporting requirements for researchers. NIH’s National Center for Advancing Translational Sciences (NCATS) received authority to support Phase II clinical trials on promising therapies. And experts at NIH and other federal agencies applauded curbs on red tape designed to facilitate staff participation in scientific and medical meetings. 

	Now FDA faces the daunting task of preparing the many new guidances and establishing new procedures within the tight timeframes specified in the legislation. One complication is that the additional $4.8 billion provided over 10 years for NIH and $500 million for FDA is authorized by Congress, but not appropriated, opening the door to future cuts in promised resources for FDA to carry out these many requirements. 

	FDA’s need for additional resources to implement “Cures” and to efficiently evaluate new medicines makes it doubly important for Congress to reauthorize user fee programs for drugs (PDUFA), biosimilars (BsUFA) and generic drugs (GDUFA) well before they expire  on Sept. 30.  Normally, enacting legislation as extensive as Cures would make the process easier, as the new law already tackles some controversial issues, such as greater reliance on real-world evidence in regulatory decision-making, expansion of priority review voucher programs to incentivize drug development, and increased flexibility for pharma companies to present information on unapproved drug uses to knowledgeable payers and formulary committees. 

	But the user fee bills need to be moving forward by summer for FDA to avoid issuing pink slips to staffers supported by fee revenues. Legislators on both sides of the aisle are looking to add on provisions to curb high prices on new and old drugs, and new Trump administration officials in HHS and FDA may want to revise the fee packages-something that FDA and industry representatives adamantly oppose after spending the last two years negotiating the new fee program agreements.

	Timely renewal of user fees is important for maintaining an efficient system for evaluating and approving clinical development protocols and market applications, which suffered a decline last year. The Center for Drug Evaluation and Research (CDER) approved only 22 novel medicines in 2016, a significant drop from the near-record 45 new drugs in 2015, reported John Jenkins, long-time director of CDER’s Office of New Drugs (OND) before his retirement last month. This may be a temporary blip in the process, as Jenkins noted that CDER continues to approve most new drugs in the first review cycle and provides expedited action on innovative drugs and breakthrough therapies. 

	A key factor in the decline, however, was a drop in new applications filed by sponsors in the first place. And more of those were incomplete or inadequate, as seen a sharp rise in Complete Response letters (CRs)-14 in 2016 compared to just a few in most years. Most CRs reflected inadequate safety and efficacy data, but manufacturing problems halted action on a notable number of new  drugs. 

	CDER Director Janet Woodcock hopes to address some of the review and approval issues by implementing a pharmaceutical platform for new drugs, along with clear data standards for drug submissions and effective IT policies, to better manage the review process.

The needed resources to implement "Cures" legislation makes it critical that user fee programs for drugs are reauthorized well before they expire on Sept. 30.

‘Cures’ Implementation, User Fee Renewals Key to Boosting R&D and Approvals

	You may have noticed that many conferences lately have been offering “Innovation Theaters,” “Innovation Showcases” or “Innovation Corners” that reserve presentation slots for many familiar technology and service companies to “showcase (their) products and services” in a special area on the exhibit floor. The primary entry criterion appears to be being first in line to pay an extra fee-there didn’t seem to be any obligation to prove actual innovation value. I believe I heard one presentation at a recent conference was actually touting “paperless” as an innovation.

	Of course, it doesn’t take much detective work to find claims of innovation. It’s difficult to imagine anyone being in this business who wants to label themselves “same old, same old” instead. Indeed, many technology and service providers use “innovation” as just another technological buzzword

, a kissing cousin, if you will, to “Big Data” or “Cloud Computing.” 

	Sometimes it seems as if jumping on a bandwagon (especially a fast-moving one) is all it takes to be innovative. But if everyone’s doing these things (or at least saying they are) can any of them really be all that innovative?

	“Innovation” is defined by Merriam-Webster.com as: 

“The introduction of something new” or “a new idea, method, or device.” 

	So fine, it’s new. But doesn’t it matter if it’s new to me (such as my shiny new smartphone, which is already a generation old to others), new to you (which depends on how much you knew previously) or, above all, new to a historically conservative industry that desperately needs to embrace dramatic change across the board in order to remain viable?

	And if newness is all that matters, I guess every teenager posting today’s selfie can claim to be innovative, too. 

	Which brings me to another, more rigorous definition offered by author Scott Berkun who has railed against misuse of the term for years: “Innovation is significant positive change. This is a high bar, and it should be. To call every little change you make in your work an innovation belittles the possible scale of progress.  It’s hubris.” 

	Today there’s plenty of talk about innovation in medical research. We have efforts to push for more funding for the precision medicine initiative, Congress moving forward with the 21st Century Cures Act, and FDA interacting seemingly everywhere toward the advancement of regulatory science. 

	But which technology and service providers in the clinical research ecosystem are really offering unique, new solutions that are truly innovative so as to impart significant positive change? 

	On the other hand, there’s plenty of support for the Luddite position. According to the findings of a PA Consulting Group innovation survey, 46% of senior executives describe their innovation activity as a “costly failure.” If Mr. Peabody were a pharmaceutical or 

biotechnology executive, he might say, “Sherman, set the Wayback machine back to yesteryear-and leave it there.”

	How can we reimagine research using our new capabilities to apply real-world evidence, patient engagement and collaborative technologies while retaining the proven gold standard of a more efficient randomized controlled clinical trial? 

	Can’t we find ways to use all of our ideas, tools, capabilities and experience to generate some meaningful disruption and actually make some positive great leaps forward?   

	So what truly innovative ideas in clinical research products or services have you seen recently? And do they meet Scott Berkun’s high bar? Let’s keep the dialogue going.

 is Chief Technology Officer, Health Level Seven International

A Closing Thought

With the term "innovation" a buzzword du jour these days, the important quest for industry is to reimagine R&D using its new capabilities to apply real-world evidence, patient engagement, and collaborative technologies.

Searching for Innovation in Research

	The adoption of select patient engagement initiatives is making steady progress but not without encountering substantial headwinds. 

	According to a 2016 CenterWatch survey of 95 major and mid-sized pharmaceutical companies, nearly two-thirds of sponsors report that they are facing pushback on implementation. Survey respondents identified three primary challenges: 57% reported

 internal resistance to modifying current drug development practices and processes; 40% noted the lack of internal expertise required to manage adoption; and 35% reported that there was insufficient funding to cover the investment required.

	Although the virtues of patient engagement are profoundly obvious to many, according to that same survey, internal resistance was strongly associated with senior management concern and uncertainty around the financial value of patient engagement. Two recently completed studies-one a retrospective assessment and the other a prospective modeling exercise-should help inform senior management about the financial return on patient engagement.

	Throughout 2016, the Drug Information Association (DIA)-in collaboration with the Tufts Center for the Study of Drug Development (Tufts CSDD)-met with 22 pharmaceutical companies and contract research organizations (CROs) to gather baseline data on patient engagement practices and their impact. The study also looked at guidelines and frameworks designed to assist implementation planning. The results of this study are being presented at conferences and webinars and can be accessed on the DIA 

	The working group conducted surveys and interviews, collected case studies of actual patient engagement initiatives and reviewed the published peer-reviewed and trade literature. The most widely adopted engagement initiatives among the working group 

companies involved soliciting input from patients and professionals to inform protocol design feasibility, clinical trial positioning and implementation. Seventeen of the 22 companies reported routinely implementing and piloting patient advisory boards. Sixteen companies reported implementing and piloting advisory panels with investigative site staff and health care providers. 

	Thirteen of 22 organizations reported that they are routinely implementing and piloting the distribution of non-technical plain language clinical trial results summaries to their clincial study volunteers. 

	Other more commonly adopted initiatives include the use of home nursing networks (9 out of 22); the conduct of surveys among study volunteers during and after clinical trials (9 out of 22) and the use of wearable devices (8 out of 22). Seven companies reported piloting, and 11 companies indicated that they are planning to use electronic informed consent.  

	The working group observed a wide variety of organizational models used to manage patient engagement initiatives. The most prevalent model was a dedicated and centralized function with the following primary responsibilities:

		Facilitate cultural change within the organization 

		Build policies, guidelines, processes and tools 

		Share effective practices across the company

		Advance more systematic patient-centric practices company-wide

		Facilitate and coordinate implementation

		Manage internal alignment of patient engagement and advocacy outreach efforts

	In total, 121 case examples of patient-centric initiatives were gathered and analyzed. These case examples produced 650 metrics in total, of which 260 were quantitative in nature. 

	The working group was unable to aggregate the quantitative metrics across the case studies to derive average impact measures and to make meaningful comparisons. 

	At this time, companies have neither defined nor collected metrics uniformly. 

	Patient and professional advisory boards, social media engagement and patient education programs were among those offering the highest return on engagement. These initiatives required minimal investment, were relatively easy to implement and had a significant reported impact, including faster study planning, approval and initiation time lines; higher randomization, recruitment and retention rates; fewer disruptions and delays; and more positive study volunteer satisfaction levels.

	Wearable devices, home nursing networks and telemedicine generally provided a strong but relatively lower return on engagement, as they required larger upfront investment and more substantial technical and operating support to implement. Impact measures showed improvements in enrollment and retention rates.

	The DIA website provides a detailed summary of 12 patient engagement initiative categories for which case-example metrics were gathered. The website also provides a Return on Engagement Toolkit for sponsor companies to apply to measure the impact of their own initiatives.

	The Clinical Trials Transformation Initiative (CTTI) funded a project in 2016 to model the value proposition of patient engagement. Project members included representatives from several pharmaceutical companies, Duke University and Tufts CSDD, and CTTI. The aim of this study was to apply a widely accepted financial modeling method commonly used by high-risk, R&D-intensive industries to guide portfolio planning and investment.

	The model components include factors that drive project value or net return- such as the revenue generated following a successful commercial launch; the direct and indirect total development and commercialization costs; the cumulative development cycle time duration; and the probability of success due to technical and regulatory risk.  

	The CTTI team developed base-case models of typical Phase II and Phase III oncology development programs using benchmark cycle time, cost and risk data gathered, maintained and published by Tufts CSDD. The model outputs included both net present value (NPV) and expected net present value (ENPV) estimates. The former is defined as the after-tax, inflation-adjusted present value of incoming and outgoing cash flows, assuming regulatory approval and market launch. 

	NPV estimates vary depending on the outcome of clinical trials at each phase of development and the risk that each potential outcome represents. ENPV combines all of the individual NPV estimates to derive an average, aggregated, risk-adjusted measure.   

	Base-case NPV and ENPV measures were compared to those following adjustments to the model. Patient-centric initiatives are expected to improve the relevance and executional feasibility of study protocols and to enhance the study volunteer experience. The CTTI team assumed that select patient-centric initiatives (e.g., patient and professional advisory panels) may result in the avoidance of one Phase II or Phase III protocol amendment. 

	On average, according to a 2016 Tufts CSDD study, a single amendment adds 90 days to the development timeline and requires $141,000 and $535,000 in direct Phase II and III costs, respectively, to implement.  

	Using the base-case model, and assuming that a modest $50,000 expenditure to implement a patient engagement initiative will result in one less Phase II and III protocol amendment, the NPV for a typical successfully launched oncology drug increases dramatically: +$25 million if the impact is realized in Phase II and +$32 million in Phase III. The ENPV also increases substantially (+$15 million) when the protocol

	The ENPV increase in Phase II is more modest-+$4 million-since the measure penalizes earlier stage projects that will encounter later stage risk. Still, in all cases, a modest investment in a given patient engagement initiative that leads to the avoidance of a protocol amendment will yield a return on that investment many magnitudes greater.

	The CTTI team also tested the prospective NPV and ENPV impact on patient engagement initiatives driving faster recruitment rates and higher retention rates. The results again indicate very high increases in NPV and ENPV based on modest investments. It’s important to note that the model is not measuring the strategic value of patient engagement initiatives-such as improvements in relationships with patient communities and better long-term positioning within a given market.

	The results of this prospective valuation model will soon be published in a peer-review journal. Refer to the CTTI website (https://www.ctti-clinicaltrials.org) to find this paper among a listing of papers published there.

	For the majority of biopharmaceutical companies and CROs, patient engagement practices are in their early stages. The retrospective assessment provides initial baseline adoption data, resources, insights and case study-based impact measures. The prospective assessment offers a financial modeling framework that sponsors can systematically apply and test to inform their decisions to invest in and support patient engagement initiatives. Combined, these two studies may help alleviate the headwinds that many organizations are encountering.

, MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both based in Boston, MA. email: 

Clinical Trial Insights

Recent studies may help break down barriers to implementing patient-centric initiatives.

Measuring Adoption and Value of Patient Engagement

 about clinical trials in 2017, where basically I said that clinical trials would change in three years or 2017. Well, 2017 is here and can I honestly say that they have changed significantly? In the blog, I was referring to trials becoming a more integrated part of healthcare, another option made in the continuum of treatment choices offered to patients, as well as their physicians.

	That clearly is not going to happen on a large scale anytime soon. However, there are movements in that area. For example, 

 that seek to educate physicians about potential trials for their patients or 

Clinical Care as a Research Option (CRCO)

, which would change the “equation for patients-putting them at the center of clinical trials; therefore, rebalancing the value for them to participate, not just as subjects, but active participants who have access to and understand their own data.”

	The patient at the center of clinical trials is a theme that came up during a panel convened to discuss the topic of our feature section in this issue, Technology Innovation. In this discussion, the experts first flipped the term patient engagement to the engaged patient, thus reflecting a more active participant in their healthcare choices more accurately. The engaged patient was at the center of many innovations in technology, either directly or indirectly, but ultimately in the final discussions, the engaged patient was one transformational factor in The Clinical Trial of Tomorrow. 

	In Ken Getz’s Clinical Trial Insights this month, he shares retrospective and prospective data that proves the value of patient engagement initiatives in clinical trials. This data, as Getz notes, can be crucial in helping change the internal mindset of senior management, who largely believes that investments in patient engagement initiatives may not have a high ROI. 

	Patients, subjects, participants....let’s be clear, the difference is where and how you get your treatment. But the bottom line is we are all people and at some point in our lives, we are going to be a patient. And at another point in our lives, we may be a subject. Getting to that place of seamless integration of options is not easy. But when you look at The Clinical Trial of Tomorrow, you can visualize how that happens. Take current data sources, make them larger and of higher quality, with standards to share, using analytics and intelligence to apply information to a specific patient or disease, that finds its way to the Healthcare Environment to inform regulations, standards of care, and personalized medicine to the patient, who owns his or her own data, and shares it with privacy and trust for research. Or start with the engaged patient and work the other way, either or any direction works because they are all interrelated.

	A huge Thank You to the technology innovation panel members who discussed the topics in detail to arrive at The Clinical Trial of Tomorrow matrix. They get the Engaged Patient, and see the path to the future is paved with more than good intentions. 

From the Editor

Reaching the point of seamless integration of patient-care options won't be easy, but you can visualize how to get there through the prism of the "Clinical Trial of Tomorrow/"

How We Get to the Engaged Patient

Clinical trials often serve as the first point of interaction between a patient and a sponsor company. Nevertheless, clinical teams can lose sight of this fact when designing the technical components of clinical studies. The outcome can be cumbersome trial protocols adding unnecessary burden on patients already in a challenging situation, and, therefore, unhappy patients, low recruitment and high dropout rates, as well as low scores on company perception surveys.

	The intent of patient-centric clinical trials is to lessen the burden of participation by making the participant journey as convenient and pleasant as possible, and, therefore, help in addressing the issues above.

	While terms such as “patient centricity” and “patient-centric trials” have become industry buzzwords and made their way into various publications and oral presentations, there is still much to do when it comes to implementation. The aim of this article is to provide practical overview on what clinical trial managers (CTM) can consider in their work to take a step toward patient-centric trials today using the current clinical trial model. 

	In a theoretical example, a CTM is accountable for a high-profile trial within a new therapeutic area for their organization. The company’s 2017 corporate goal is continuously on display throughout the office: “all staff are to implement goals and measures related to patient’s satisfaction and loyalty.” By measuring patient satisfaction across the organization, executive leadership anticipates the establishment of a baseline understanding of how the company is perceived by its most important stakeholder, the patient.

	It is easier said than done: the only patient satisfaction data you have, in this example, is from an orphan drug Phase III trial a year ago, in which retention rates were disappointingly low. Participants complained of challenging visit schedules and poor communication of the trial intent, design, and outcomes. Consequently, the study was delayed and over budget. Most companies have looked only at cost, timelines, and quality of results, not patient or site experience. But patient and site experience plays an important role in all of these factors. You want to execute a successful trial by implementing a more patient-centric approach. How can you make the clinical trial journey more efficient and less cumbersome for the participants and clinical staff? 

	Figure 1 below illustrates gaps in the trial continuum from a participant perspective. By adequately addressing the gaps at every phase of the process, a CTM can help ensure that their trials are designed in a way that is not just scientifically rigorous, but also incorporates patient perspectives.

	Improvements in patient-centricity can be made throughout drug development and life cycle management, from trial planning activities to product launch. Trial planning activities may include live protocol simulations, patient advisory boards and other ways of soliciting patients and caregiver input on what a trial should include, and protocol review committees with key cross-functional stakeholders outside the organization (including patients and patient advocacy organizations). Some companies use crowdsourcing at the protocol development stage to gain patient insights on the protocol, including endpoints and procedures. By thorough planning that prioritizes the participants’ trial experience, CTMs can help ensure that they are considered stakeholders in the trial experience and results. 

	The quality, timelines, and, therefore, the cost of a trial is significantly affected by the commitment of the participants to achieving a successful trial. This commitment increases with a deeper understanding of trial requirements, and, thus, willingness to follow all trial routines, such as regular attendance of trial visits, timely and detailed reporting in patient diaries, and the quality of patient-reported outcomes. Although the FDA has not developed specific guidance on all possible aspects of patient-centric trials, the agency does emphasize the importance of incorporating patient perspective in the development and evaluation of new medicines and has several 

	Incorporating the patient perspective into trial planning and activities is not an easy task that can be done by the CTM alone. However, unless an organization has a function dedicated to patient-centricity, the CTM will need to be the driver and ensure that the appropriate internal and external stakeholders are at the table. The person may also need to assist in the development of guidance and policies for his or her organization, particularly regarding compliance and the selection of third-party vendors. Success depends on the support of multiple groups in the organization, including legal and compliance, regulatory, corporate communications, medical research, and medical affairs. Outside the company, buy-in from external patient advocacy groups and clinical trial sites will be needed to complement the company’s support. If a CTM runs their study with a contract research organization (CRO), it, of course, will need to be involved from the get-go. 

	For maximum impact, the CTM can do the following:

		Review patient-centric approaches used by other companies in the same therapeutic area: what can you earn from current practice and outcomes? 

		Mindfully assess eligibility criteria to ensure they are not too restrictive 

		Mitigate unnecessarily complex protocols by involving the patient in the design process 

		Start the clinical trial planning process early, ideally 10 months prior to trial launch, to ensure time for refining and implementing the patient-centric approach 

		Build in additional time and budget for training of site staff

		Track the changes that incorporating a more patient-centric approach makes to timelines and budget

		Collect evidence to make the business case for patient-centric measures to your supervisors: enrollment and dropout rates, budgets, timelines

		Above all, consider the clinical trial patients’ journeys-how patients are making their decisions about trial participation-throughout the planning process  

	During the planning process, cultural differences should be considered. In the era of global clinical development, patient communication and trial materials must be created with cultural differences in mind and available in multiple languages. Better results at local sites will be achieved if staff are empowered to put necessary customizations in place. Patient registries can also help sponsor companies improve the post-trial relationship with participants. The role of a global CTM is to work with local colleagues to ensure these nuances are considered throughout the clinical trial phases. 

	Throughout trial start-up, recruitment, and retention, thoughtful communication with participants is essential to the establishment of patient-centric practice. Before the trial even begins, companies should publicize the trial appropriately, through government websites, patient advocacy and treatment center websites, and, as appropriate, mass advertisement.

	Make your sites partners in the trial by soliciting their input and providing training and materials before recruitment begins. Their role is critical; they can make the journey for the patient less complicated and more rewarding. From the start, remind your sites to convey the concrete benefit to a participant in culturally-appropriate ways: that he or she is often getting even more attention and oversight of their care while they are in a clinical trial, even if they receive the placebo. Schedule regular patient experience evaluations in addition to standard clinical assessments. The CTM can help ensure that the sites (with the support of the sponsor) can provide input on local culture and have the materials they need to include participants as active partners in advancing critically important research. Acting mindfully, a CTM has a chance to help sites make participants true partners in the trial process.

	Above all, emphasize that two-way communication between site and participant is the priority. This principle should inform the “toolkit” a CTM provides to their sites so that they can do the following effectively: 

		Get participant feedback before executing by asking questions about scheduling, etc.: “Will this be onerous for you?” Sites need to look several steps ahead to allow for patient schedules (work/family)

		Set participant expectations: these are the responsibilities and rights as a participant. Always offer to include the participant’s caregiver (if any) 

		Discuss and explain protocol endpoints and other scientific aspects of the trial with participants before, during, and after the trial 

		Explain expected protocol operational hurdles and opportunities to participants; solicit their advice on addressing these issues

		Ensure that the sites have easy means of providing feedback throughout the trial. Timely feedback can help the CTM and sites address unforeseen problems that arise before the trial is negatively impacted

		Explain that it is the participant’s responsibility to keep the study blind. They are essential members of the team 

		Cultivate patient loyalty: anticipate their questions and objections and have answers ready in lay language

	Once the trial is underway, similar strategies and tools can improve patient retention. In addition to providing standard appointment reminders, CTMs can use e-diaries, wearable devices, and even “bring your own devices” (BYOD) to make participation easy, collaborative, and interactive.

	BYOD allows participants to use their own devices, like smartphones and tablets, to complete study assessments, such as monitoring daily activity and collecting patient reported outcomes (PRO) and quality of life data. The BYOD devices approach may also be used to enhance communication with study participants through easy and virtually no-cost measures, such as sending out study visit reminders or sharing individual trial data.

	BYOD has recently been evaluated, by Bracket, in a Phase II Parkinson’s disease clinical trial. Results were presented at the Annual DIA Meeting in June 2016. Participants used an application that included a mix of surveys and tasks. The active phone sensor collected and tracked their progress. Over the course of the study, adoption went up and, by the end of the trial, 80% of the data was submitted via the app. Adam Butler, Bracket’s Senior Vice President for Strategic Development, expects to see a “tipping point of very heavy adoption” of BYOD in clinical trials over the next three to five years.

	Participants that feel involved in the process through these strategies may even offer more and better feedback. With sufficient funding and staffing for the sites, CTMs can go even further by incorporating home visits by site staff and/or healthcare professionals. Including these strategies in trial design can help CTMs create and manage patient-centric programs that can lessen the burdens on the participants and improve results. 

	Once participants are chosen, communication toolkits for the sites can help staff establish a more personal relationship between patients and the company through basic low-cost components such as a welcome letter and information about the trial in lay language. Other ways in which the CTM can improve the participants’ experience include the following: 

		Engagement and community building, via patient associations, face-to-face advisory boards via third parties, surveys, social listening, and other channels

				Participant newsletters and brochures written in lay language

				Talking points for the sites to supplement these materials

	As simple and inexpensive as these measures are to execute, surprisingly, most companies do not provide them to participants consistently. CTMs can step up and fill this gap to begin establishing a patient-centric experience for participants from the first interaction.  

	Carrying the patient-centric principle through the post-trial period is critical. CTMs can play a role managing this process. For example, a simple “thank you” for trial participation can go a long way and help a patient consider participation in a future study. Sharing trial results in a lay language improves the company-participant relationship. It is also the right thing to do from an ethical point of view. Still, most patients do not receive information regarding the outcome of the trial they participated in or of the important role that they played.

	Patient-centricity may lie beyond the scope of a typical development program. Collecting real-world, long-term data is critical and can be achieved via patient registries. While the idea sounds simple and not new, there are still a lot of questions when it comes to how. The Clinical Trial Transformation Initiative (CTTI) has a work-stream underway to develop recommendations with the aim to increase use of patient registries in clinical research.

	The main intent of assessing these measures is to understand the percentage of participants touched by patient-centric tactics. This will guide CTMs for upcoming trials by identifying what innovations work best. A CTM can also, at the end of a trial, ask for direct feedback from participants, via a third party, on the patient-centric activities that were implemented. Keep in mind that you might see cultural and regional differences for which you should account in reviewing results. The following participant information from the sites can help a CTM understand results, refine techniques for future trials, and report learnings to   colleagues: 

		Percentage provided insights on protocol, endpoints, and operational hurdles to overcome 

		Percentage educated about the general trial journey and the one they are to consider joining

		Percentage informed about trial progress 

		Percentage that were part of a trial community 

		Percentage that received a thank you from the sponsor via the site 

		Percentage that received lay language summary reports of trial outcome via the sites 

		Follow-up by sites, with a CTM’s guidance, can include the following:

		Identifying areas in which participants need further education on the clinical trial journey in general and for the protocol specifically

		Conducting participant surveys during and after the clinical trial

Feature Article

A how-to guide for clinical trial managers in implementing patient-centric approaches using today’s clinical study model.

A Practical Overview of Patient-Centric Trials

The use of electronic clinical outcome assessment (eCOA) represents a mechanism of capturing both patient and clinician reported outcomes digitally instead of on paper. The most common use of eCOA is for data capture in clinical trials. The evidence for obtaining improved data quality with digital systems over paper has grown substantially and as such, avenues for using eCOA in healthcare are being explored. eCOA captures data on handheld smartphones, tablets, browsers, interactive voice response systems, and patient’s own devices (bring-your-own-device, or BYOD), using secure systems that meet regulatory guidelines for electronic capture of clinical data. Consent for clinical trials details patient privacy, explains how the trial will be conducted, and confirms that the clinical site owns all clinical research data. The patient may authorize trial access to their lab, imaging, and electronic medical record (EMR) data for integration with their study data.

	As adoption and the use of eCOA grows, additional learnings have provided a more complete understanding of how to use it effectively in order to derive the benefit of improved data quality. Herein, we will discuss the evidence of how the use of eCOA can promote increased communication between patients and clinical staff, increase patient reporting of events, and how tools such as training and patient engagement should be implemented to deliver maximal benefits from the use of technology. Collecting high quality data for clinical research requires a blend of clinical science and technology. Clinical science influences patient engagement behaviors with study design, collection schedules, predictive instruction, and assessment selection.

	As more questions arise about improving patient engagement in clinical trials, many sponsors are finding that the answers may lie in the use of technology. Most pharmaceutical companies are considering methods for implementing novel technologies (e.g., activity trackers and mHealth devices) in their trials, in order to maintain better, more consistent interaction with study subjects. Many of these devices are still in proof-of-concept testing. Whether they will find their place in clinical research will be the decisions of global regulators. The US 21st Century Cures Act mandates that FDA regulate accessories based on their intended use, instead of based upon the parent device with which the accessories are associated. 

	What many sponsors may not realize is they already have access to regulatory-approved technology that can address current patient engagement challenges. Researchers will find that the use of eCOA not only improves data quality, but also offers the potential to improve patient engagement during clinical development.  

	The benefits of capturing high quality clinical trial data via eCOA have been widely recognized for more than a decade. Researchers have documented significant improvements in patient protocol compliance and data quality, a reduction of missing data and data “noise,” and, most importantly, increased study power with fewer patients.

	Here we review some of the well-established literature demonstrating how eCOA can also improve patient/clinician communication and candor vs. traditional paper-based COA, helping sponsors to keep patients better engaged during clinical development.

	eCOA prompts and increases patient/clinician interactions and enables subjects to think through their symptoms prior to meeting with site staff. As a result, patients are more likely to bring up clinical events in discussions with the clinical site, since the eCOA completion prompts their memory of additional details. For example:

		In a head-to-head comparison of electronic vs. paper completion using the EORTC-QLQ-C30, 48.9% of the symptoms reported electronically were addressed at the clinic visit vs. only 23.6% on paper.

		In a study of 660 cancer patients, patients were given touch-screen tablets to complete electronic self-report assessments, which included items on symptoms and health-related quality-of-life. The results indicated that 

electronic patient-reported outcome (ePRO) reports to clinicians fostered discussions with patients at visits, clinicians were more likely to discuss issues flagged by the automated system at visits, and visit duration was unaffected.

		Electronic COA ensures that every patient is asked the same questions in the same order at every visit without bias, halo, error, leniency, variation, interpretation, or mood. These electronic data are then available for site staff to intervene, augment, and guide care. 

	Reporting of more (and more severe) events

	eCOA has been proven to increase patient candor. Patients are more likely to report more (and more severe) events electronically than on paper. This principle applies across a spectrum of indications and is generally applicable to patient-reported data. Patient reporting on diverse topics such as medication compliance and blood glucose levels are common examples.  

		Diabetes subjects under-report hypoglycemic and hyperglycemic events on paper COAs 67% of the time.

 Further, diabetic patients using paper COA capture blood glucose values but fail to record them. A systematic review encompassing 11 diabetes studies showed that among these three categories of errors, nearly 50% of paper COA data was inaccurate.

 Electronic COA mitigates any such errors because the blood glucose readings being captured via fingerstick monitoring are wirelessly transmitted to the eCOA device. 

		Several studies examined the impact of electronic and paper patient diaries on glycemic control and HbA1c levels. These studies found that increased monitoring in the electronic version may have encouraged positive behavioral changes and/or provided additional information on which patients could take action to improve their glycemic control. The use of a mobile electronic diary vs. conventional clinic visits were compared in patients from a diabetes clinic in a 12-week crossover design study.

 In the electronic diaries, subjects recorded meals and blood glucose levels, then received immediate feedback on their nutritional intake. There was a significant improvement in HbA1c for the time that subjects were using the electronic diary vs. the control period (HbA1c levels reduced 0.83%). Overall, the authors concluded that use of eCOA improved HbA1c levels.  

		In another study comparing paper vs. electronic diaries, HbA1C levels decreased more in the electronic than the paper group. Furthermore, those who reviewed their electronic screens with their healthcare providers tended toward better glycemic control than those who did not.

		The eCOA diary has proven to be an important and better tool than paper for patients and healthcare providers to improve clinical care. Good control of blood glucose levels is well recognized as a key element to attenuating disease progression for patients with diabetes. Studies show that for each percentage point decrease in HbA1c, microvascular complications are decreased by 35%.

	Self-reported electronic data capture (EDC) enables increased patient candor in suicidal ideation and behavior. Patients are more likely to reveal a higher frequency and severity of symptoms than ascertained by site interviewers. These phenomena are also well documented for topics including sex, drug/alcohol abuse, obesity, HIV, and mental health.  

		In major depressive disorder and bipolar disorder, self-reported questionnaires were two to four times more likely to reveal higher frequency and severity of suicidal ideation than clinician-ascertained.

 In an eight-year study in children and adolescents, 98 families were followed (ages 5-18). Subjects completed a youth clinical interview and youth self-report assessments on suicidal ideation. Reports of suicidality were higher for the self-report group (25% and 30% in the younger and older cohorts, respectively) than the interview version (11% and 24% in the younger and older cohorts, respectively).

How the adoption of electronic clinical outcome assessment in trials can drive increased communication and patient reporting of events.

Applied Clinical Trials-02-01-2017

Investigators’ Financial Ties Come Under Close Scrutiny

Times Changing for Ethics Guidelines, too

Disruptive Innovation and the Technology Strategies Needed

‘Cures’ Implementation, User Fee Renewals Key to Boosting R&D and Approvals

Searching for Innovation in Research

Measuring Adoption and Value of Patient Engagement

How We Get to the Engaged Patient

A Practical Overview of Patient-Centric Trials

Improving Patient Engagement through eCOA

An Auditor’s View of Compliance Challenges

The Clinical Trial of Tomorrow

Applied Clinical Trials, February/March 2017 Issue (PDF)