	A main goal for FDA leaders in the coming months is to refine clinical trial design and analysis so that studies can have smaller patient populations and achieve better outcomes. With clinical research expert Robert Califf slated to take the helm of the agency, initiatives to streamline trials will be a prime area of focus in facilitating biomedical discovery and bringing more new drugs to patients.  

	A December draft guidance, for example, lays out a process for sponsors to consult with agency staff during product development. Encouraging such communication aims to ensure that biopharma investigational plans and clinical trial designs produce adequate data to support product evaluation and approval, particularly for drugs developed under expedited programs (see 

	FDA also is soliciting comments from the research community on how new technologies and innovative methods can improve the investigational process. Topics include how study participants may use personal devices, such as smartphones and tablets, in “nontraditional settings” to collect data,  and how such methods may alter informed consent procedures. Similarly, the Center for Drug Evaluation and Research (CDER) is asking sponsors and research organizations to propose demonstration projects that test the use of electronic health records and standards-based technology solutions to improve clinical trial data capture. These methods should limit errors, while reducing on-site data monitoring and other high-resource processes.

	A main policy issue for FDA and sponsors is to ensure that clinical studies assess new medical products in a broad range of patient populations. Despite years of seeking diversity in clinical trials and adequate subgroup analysis in applications, FDA and other federal agencies continue to encounter studies with limited exposure to patients with differences in age, sex, race and ethnicity. A November report from the Government Accountability Office (GAO) found that research supported by the National Institute of Health (NIH) often fails to assess outcomes by gender to determine if men and women respond differently to a test therapy. 

	FDA will hold a public meeting at the end of February to hear from the research community on how well the agency is implementing its Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, which was issued in August 2014 as directed by the FDA Safety and Innovation Act (FDASIA) of 2012. The Plan contains 27 action items for improving subgroup participation and data transparency. FDA would like input from stakeholders on successful approaches for recruiting diverse clinical trial populations, limitations in meaningful data analysis of underrepresented groups, and how best to communicate with and present information on subgroup analysis (see 

	Some of the methodological and policy challenges in ensuring diversity in clinical trials were discussed by research experts at a workshop in December 2015 hosted by FDA and the Johns Hopkins Center for Excellence in Regulatory Science and Innovation (JH-CERSI). Participants examined ways to improve the completeness and quality of demographic subgroup data collection and analysis, and to assess whether clinical trial findings are generalizability when not derived from studies of diverse populations. Key topics included barriers to enrolling subgroups in clinical trials, strategies for encouraging greater participation, and ways to make demographic subgroup data more available and transparent (see

	In a keynote address, Califf commented on a range of important clinical research issues. He noted the “inherent tension” between inclusive and targeted studies and the need for balance between clinical trials large enough to assess all relevant populations, and sufficiently small to provide deep data on each patient. He also observed that the challenges in conducting complex studies may be alleviated by greater use of electronic health records to obtain information on treatment impacts, and by tapping non-randomized epidemiological data to draw causal inferences about the presence or absence of a safety issue in a sub-population. 

	Social media also may be helpful in identifying meaningful outcomes for diverse populations. “It’s not just who we go out and include, but how we bring people from diverse neighborhoods into the design of the trials themselves” and how we identify what is important to them. 

	With more evidence coming from studies conducted outside the U.S., FDA needs to consider when to require data on U.S. populations and how to deal with differences related to geography, Califf observed. Most important, he commented, is to have well-designed clinical studies that can support the use of a product based on good evidence. Studies should be published in journals and posted on the ClinicalTrials.gov. website and then submitted to FDA for independent evaluation. FDA decisions are critical to whether a product gets to market-“and we very much want to stay as the gold standard for that.”

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Agency is asking sponsors to propose demonstration projects that test the use of electronic health records and standards-based technology solutions. Ensuring trials assess new drugs in diverse patient populations is also a priority focus for FDA.

FDA Looks to New Techology, Policies to Streamline Clinical Research

				The European Medicines Agency (EMA) has ratified a new approach to measuring the impact of pharmacovigilance activities, covering how to gather data and knowledge on the effectiveness of measures and processes meant to ensure the safe use of medicines for patients in the European Union.

				Following the recent incident in Rennes, northwestern France-in which a Phase I trial involving private laboratory Biotrial and Portuguese pharmaceutical company Bial went seriously wrong, reportedly leading to five hospitalizations and the death of one volunteer-this strategy is bound to generate considerable interest.

				The new approach adopted by the EMA’s Pharmacovigilance Risk Assessment Committee builds on existing activities in the member states and the agency, and relies on collaboration with stakeholders. It focuses on four areas: measuring the effectiveness of risk-minimization measures on specific products; measuring the effect of specific pharmacovigilance processes (e.g., spontaneous reporting of suspected adverse reactions, signal management); investigating how to ensure engagement of key stakeholders (e.g., patients, healthcare professionals); and further improving methodologies to determine the effect of pharmacovigilance activities on public health.

				The strategy includes an overview of activities and deliverables for implementation, along with a summary of the objectives for the next three years and a detailed work plan for 2016.

				According to a statement issued by the EMA in January, among the current safety methods used in Europe are proactive planning of risk-minimization measures before a medicine is authorized; the collection and management of suspected adverse reaction reports; the detection and management of potential new safety signals for medicines; and the planning of post-authorization studies to generate data on the use of medicines in the real world.

				“As new information emerges from these activities, regulators may take further actions to minimize risks,” the agency stated. “They can, for example, inform and advise patients and doctors on the best use of this medicine or restrict the use of a medicine in case the medicine’s benefits no longer outweigh its risks in a certain population.”

		The EMA added that assessing the impact of pharmacovigilance allows regulators to determine which activities are most successful and helps promote best practice.

		The agency has also published its revised policy on handling competing interests for members of its management board. The policy, which aligns EMA’s management board policy with the agency’s policy on handling declarations of interests for scientific committee members and experts, will become effective on May 1.

		“The effective management of competing interests of management board members is critical to ensuring the independence of the decisions of the board,” said Noël Wathion, EMA’s chief policy adviser. “The updated policy brings the rules for board members in line with those for scientific experts, while also taking into account the specific role of the board, without lowering the bar on the independence of its work.”

		To ensure its scientific experts, staff, and management board do not have any financial or other interests in the pharmaceutical industry that could affect their impartiality, EMA has continuously reviewed its policies over the past few years. The board takes strategic decisions and supervises the corporate activities of EMA, such as setting the budget and approving its annual work program. It does not give recommendations on marketing authorizations of medicines.

		For a EMA board member with a declared interest, the agency will apply a “risk-based” approach to determine the level of involvement in the activities of the management board. The approach will be based on four factors: the nature of the declared interest; the timeframe during which the interest occurred; the type of management board activity; the likely impact of the board’s decision on the pharmaceutical or other industry; and the type of action requested by the management board (e.g., whether a decision such as approval or endorsement has to be taken by the board or not).

		The current “breach of trust” procedure on declarations of interests for management board members has also been revised. It was approved in December and went into effect on Jan. 1. The changes are linked with those introduced last year for the breach of trust procedure for scientific committee members and experts. The breach of trust procedure was developed in 2012 to deal with cases of incorrect or incomplete declarations of interests of board members.

New approach focuses on assessing the effectiveness of four key areas related to risk-minimization and pharmacovigilance activities in Europe.

EMA Adopts New Strategy on Measuring Impact of Pharmacovigilance

	There’s no doubting the energy and ambition of the European Medicines Agency (EMA). Its own summary of its achievements in 2015 is eloquent testimony. Highlights in its core activity of evaluating human medicines include 93 drugs recommended for approval, including for 39 new active substances. It was, says EMA, “an important year for public health in the European Union”-citing “innovations that have the potential to make a difference to people’s lives” in cancers, cardiovascular diseases, hematology, and neurology.

	The EMA summary also notes other aspects of its work-including continuous checking of drug quality and safety (or, as the agency describes it, a new public-friendly choice of language, “monitoring the benefits and risks that patients experience with this medicine in real life”), ensuring the integrity of the  development and manufacturing of medicines, and updated advice for HIV patients.

	But EMA’s principal boast relates to its role in promoting healthcare innovation. And not just with the 39 new active substances. The use of an already approved medicine in a new therapeutic indication can also offer new opportunities for patients, the agency stresses, going on to list half a dozen key examples from the past year, including Perjeta for patients with breast cancer undergoing surgery.

	Perjeta (pertuzumab) is a Roche/Genentech monoclonal antibody, first authorized in the U.S. and much of Europe two and three years ago as part of a treatment for specific cases of breast cancer, where the protein HER2 is found on the surface of the cancer cells, and where disease has spread to other parts of the body or has come back after treatment. The drug received EMA approval for this indication in 2013, and is increasingly widely used. Perjeta is a rapidly growing element in Roche’s portfolio, with the company’s third-quarter report last year noting: “Sales of the HER2-positive breast cancer medicines, Herceptin, Perjeta, and Kadcyla, grew 19%.”

	As the EMA remarks, in 2015 Perjeta’s indications were extended. The new authorized use includes treating earlier stages of breast cancer at high risk of coming back, where it is locally advanced or inflammatory, so as to improve the chances of surgery-neoadjuvant therapy. The EMA evaluation of Perjeta in neoadjuvant therapy indicates the drug “was shown to improve response to treatment.” Despite some side-effects, “the overall safety profile was acceptable.” EMA “decided that Perjeta’s benefits are greater than its risks and recommended that it be given marketing authorization.” The FDA approved use for neoadjuvant treatment in 2013, under the agency’s priority review program, which provides for an expedited review of drugs that may offer major advances in treatment.

	But the EMA’s view of these “new opportunities for patients” is not universally shared. At the end of 2015, just six months after this additional indication received its ringing endorsement from Europe’s top scientists, a diametrically different view emerged from Europe’s most important organization advising payers on which drugs merit reimbursement, the Institute for Quality and Efficiency in Health Care (IQWIQ), which does the groundwork for the reimbursement authority in Europe’s biggest market, Germany,  

	According to IQWIQ, the supporting data for neoadjuvant use contains a “hint of lesser benefit,” and there is “no proof of positive effects.” Although IQWIQ assessment in 2013 of Perjeta’s initial use found “a survival advantage for certain patients and, hence, a hint of a major added benefit,” the advice it has given for neoadjuvant use is that “the study data presented resulted in a hint that pertuzumab is of lesser benefit than the appropriate comparator therapy.” It also questioned the relevance of the data supplied. There is only “limited transferability of the study’s results to the German healthcare context,” it said.

	There may seem to be something odd about such a discrepancy of view to anyone unfamiliar with the arcania of European authorization and reimbursement processes-and even to those who are inured to the complexities. On the face of it, the difference of opinion seems hard to understand. Even the company itself (and Roche is hardly a newcomer to European procedures) observed with scrupulous restraint that this opposition was highly unusual. “It’s the first time that we’ve received such a divergent view by IQWIG in regard to the EMA approval,” the company said in answer to questions-adding that the product was accepted in this usage in the U.S., too. “With the early approval of Perjeta in the neoadjuvant setting, both the FDA and EMA have acknowledged the need to bring new efficacious treatments to patients,” Roche said.

	But Europe is Europe, and operates in its own quaint way. The EMA downplayed the issue when questioned on the coherence of European decision-making. “The assessment methodology as well as the purpose of the assessments carried out by EMA and by health technology assessment (HTA) bodies are very different and cannot be compared,” the agency said, providing 

an extensive background review of the distinct roles of authorization bodies and HTA organizations. And it neatly sidestepped further queries with the careful disclaimer that “EMA cannot comment on the assessments made by HTA bodies in the member states.”

	Within Europe’s industry associations, hard-headed realists also hesitate to draw conclusions from this apparent clash of views. Pär Tellner, regulatory affairs director at the European Federation  of Pharmaceutical Industries and Associations, said the question was not whether IQWIG is or is not scientific, or less scientific than the EMA. “HTA and regulatory agencies have different remits,” he pointed out. While the EMA assesses the safety, efficacy and quality of products, providing for a range of alternatives to patients, HTA agencies “consider the alternatives that are available and, in light of their national priorities, support decisions on which alternatives should be made available/reimbursed for which patient groups, and at what level,” Tellner said. “Therefore, conclusions from the HTA review and EMA review might very well differ.”

	But even allowing for the distinct roles of regulators and HTA bodies, disarray in Europe over getting new medicines to patients is certainly provoking interest at high levels of the European Commission. A recent working document bearing the strong imprint of Commission President Jean-Claude Juncker expresses unambiguous concern over “the limited standardization and coordination of the HTA process in Europe.” It underlines that “with currently about 50 HTA agencies in Europe (including national and in some countries regional agencies), fragmentation is very high,” as “multiple stakeholders and systems apply varying requirements.” It says the varying results between countries raise the question of objectivity and accuracy of assessments, and compromise rewards for innovation. “Shortcomings in HTA coordination … can have negative effects by delaying patients’ access to innovative treatments,” the Commission’s document says. 

	Pharmaceutical policy theologians can accurately and adequately explain and even justify what look like contradictions. But the question is being examined not solely by theologians. German patients might well come to question why they should be debarred from a benefit flagged up so enthusiastically by the EMA. They may not be so willing to accept that the system must be accepted as it is. They-and many other patients in many other European countries seeking access to many other treatments they are currently debarred from-may wish to see changes, and changes at a pace greater than the current discussions between industry, EMA, and HTA bodies envision.

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

View from Brussels

Incoherencies in Europe’s drug-access arrangements raise questions, debate.

Ambition vs. Assessment: The Approval-Reimbursement Divide

	According to an October 2015 Gartner Group report,

 by 2017 less than 10% of clinical trials will incorporate a wearable device. The success, Gartner analysts believe, hinges on the ability to integrate wearables with data exchanges and cloud-based analytics, and connection to e-clinical systems. 

 and SCORR Marketing set out to uncover wearables usage in clinical trials among our audience. The resulting report from our joint survey was produced by SCORR and is available for free download 

	Slightly more than half of our respondents are aware there are current pilot studies being conducted with wearable technology. For example, Medidata 

last June announced the results of its behavioral study in overweight adults with type 2 diabetes. According to the company,

 the MOVE-2014 study participants exhibited high compliance with charging and using the mobile devices, which included wearable activity trackers and smartphones. The study also showed that quantifiable, objective data could be securely pulled from the devices into its Medidata Clinical Cloud® platform-and integrated with other clinical trial information-in a regulatory-compliant manner.

 that it participated in an early-stage feasibility study of a wearable device-plus-smartphone application. The patients received medications, the wearable device-plus-smartphone technologies, and training to use the devices and smartphones, with the goal to test as many hypotheses surrounding the uses and types of wearable technologies as possible (i.e., smartphones provided with the study mobile app installed vs. downloading the study mobile app to the patient’s own smartphone).

	While the Gartner Group’s report is slightly pessimistic, there are glimmers of hope for the adoption of clinical trials using wearables. Our survey found that between 30% to 41% of trials were currently incorporating wearables

 for either drug delivery or monitoring. And, if our respondents predictions are correct, the majority (over 90%) believe that in three years more trials will utilize wearables and that in three years the positives of wearable technology will outweigh the negatives. 

	And what were the negatives? Our respondents were concerned with patient compliance, data validity, costs, data security, and data context in that order. According to the Gartner report, for the long-term use of wearables in clinical trials, they will need better hardware, better sensors, and tighter integration into a mobile health ecosystem that provides industry standards for maintaining health data integrity and security. 

	1. Pettey, Christy. Are Wearabes Fit for Clinical Trials? October 2015, accessed January 2016. 

http://www.gartner.com/smarterwithgartner/are-wearables-fit-for-clinical-trials/

	2. Medidata press release, accessed January 2016. 

https://www.mdsol.com/en/newsroom/press-release/medidata-completes-study-exploring-potential-instrumenting-patients-mobile

Survey spotlights the concern levels associated with the adoption of clinical trials using wearable technology.

How Do You View the Future of Wearables?

	Competition between drugs within a given class has intensified, according to a new study recently published by the Tufts Center for the Study of Drug Development (Tufts CSDD). Newly approved first-in-class prescription drugs face substantially shorter periods of exclusivity within which to recoup the high and rising cost of drug development.

	Tufts CSDD reviewed 40 multiple-entrant pharmacologic classes that produced 108 new drug approvals in which the first-in-class agent received approval between 1998 and 2011. Comparing market exclusivity periods for drugs approved between 1998-2004 and those approved between 2005-2011, the results show a 51% reduction in the median time-from 4.7 years down to 2.3 years-from when the first-in-class drug was approved to when the first competitor entered the market. Three-out-of-four second entrants in a given drug class were approved within 3.7 years and 25% were approved in less than six months. Tufts CSDD also found that nearly half (49%) of the 40 classes examined eventually had three or more competitors. 

Study shows sharp reduction in market exclusivity periods for first-in-class treatment entrants.

Competitive Pressure for First-in-Class Drugs is Intensifying

	Google handles over 1 trillion searches a year. That’s more than 33 searches a month for each person worldwide who uses the Internet. Search engine queries provide a window into people’s thoughts and questions. Using aggregate search query data, we can better understand potential clinical trial participants. And understanding is essential to improving trial education and awareness. A number of tools provide access to search data, but Google’s tools are most popular. 

	To illustrate the value of search engine data, I decided to have a little fun with Google’s autocomplete. Autocomplete is the real-time suggestions Google provides as you type a query. These suggestions are based on various factors, including prior queries from other people. Because prior queries inform autocomplete, it can provide a view of collective consciousness around different topics.

	This exercise is purely for “infotainment.” If you really want to analyze search engine data, there are better, more sophisticated ways. But this exercise is a quick and easy method for getting some high-level insights into the general public’s thoughts and questions about clinical trials.

	I’ve structured the following query examples as questions. The question format helps to elicit biases people have about clinical trials. Hence, autocomplete will provide clues not only to what people want to know, but also their preconceptions with regard to clinical studies.

	There’s much we can learn from these and other autocomplete suggestions. People’s preconceptions and questions about clinical trials can be addressed with two main types of education: basic and protocol-specific. Autosuggest provides insights into educational themes we might need to address within each of these categories. Basic themes found in the autosuggest exercise include:

		What’s involved in participation (e.g., length)?

	In recent years, clinical researchers have turned to social listening to understand patients, but social data is not the only online data game in town. As this exercise shows, search data provides a unique view into people’s thoughts and questions. Regardless of type, online data can be a quick and inexpensive form of market research.

 is Founder/Digital Marketing Strategist, Rebar Interactive, and Applied Clinical Trials Editorial Advisory Board Member

- This article is adapted from a post that appeared on the Rebar Interactive blog.

A Closing Thought

Search-engine data offers window to public consciousness around clinical trial research, participation.

What Google Can Teach Us About Trial Education, Awareness

Patient centricity is a popular trend with the potential to revolutionize clinical trials. By shifting from a product-focus to a patient-focus, clinical trials will become more relevant, less costly, and more impactful.

Patient centricity has the potential to be “biopharma’s Holy Grail” that will lead to a “renaissance” in clinical research.

	But will patient centricity ever reach its full potential? Skeptics are beginning to speculate that this approach is simply another fad.

 According to this view, patient centricity applies new jargon to standard clinical trial processes that result in high-visibility but low-impact activities.

 They admit that patient centricity has an intuitive appeal, but that it is based on jargon and ethical imperatives rather than empirical data.

	In order to allow patient centricity to reach its full potential and prevent it from becoming a fad, we must begin to scientifically measure its level of application in our clinical trials. Scientific measures will not only help us to understand the patient 

centricity of our trials, but will also provide a scientific basis for improving its role and clinical trials overall. Once we can measure the patient centricity of each trial, we can begin to understand how management interventions affect patient centricity levels, and provide a scientific foundation on which patient centricity can continue to develop and grow. But this vision all depends on a valid and reliable measurement. Preventing patient centricity from becoming a fad all boils down to scientific measurement of its ultimate impact.

	Patient centricity is a complex construct with a multifaceted sampling process. Despite these challenges, however, it is still possible to develop a straightforward patient centricity measurement program. In this paper, we will describe how clinical trial managers can begin the journey to scientific measurement of patient centricity with a three-step process. These three steps are based on the standard processes from the peer-review psychometric literature.

 As a result, we provide a scientific, valid, and reliable approach to measuring patient centricity. 

	Patient centricity in a clinical trial means designing and conducting a study-including the care of patients within the trial-in way that is respectful of and responsive to patient preferences, needs, and values, and ensuring that patient values guide all decisions within the trial.

 We recognize three important implications in this definition. First, patient centricity measurement is a component of clinical trial quality. Clinical

 trial quality refers to the overall excellence or superiority of the trial. We have previously defined quality and discussed at length in a previous article, “The Quality of Clinical Trials.”

 Responding to patients is an important aspect of clinical trial quality.

One can’t understand the quality of a clinical trial without measuring patient centricity, as shown in Figure 1.

	The second implication of this definition of patient centricity is that measurement must also include the backstage activities of planning and designing the trial. To what degree are patients included in decisions about the research question, inclusion criteria, endpoints, marketing materials, recruitment, data collection, and dissemination of the study results? Measuring patient centricity, as a result, requires assessment at two levels: a high-level perspective on the design of the trial and then individual-level evaluations of patient care. At both levels, we use purposive sampling techniques-not random sampling-to assess the right respondent at the right time. All of this makes for a complex sampling process.

	The third implication of this definition is that patient-centricity measurement also includes assessing the patient care aspects within the trial. Even though a clinical study is an experiment, it still involves caring for patients. It is important to include these care processes in patient-centricity measurement even though it is still a clinical trial.

	One of the unique features of patient care is that both the provider and the patient have to collaborate in order to deliver effective care. Each has an important role in both the patient care side and the clinical trial activities. Providers, for their part, must be responsive to patients’ preferences, needs, and values. Patient engagement refers to patients assessing providers as to how well the provider cared for them in a way that was respectful and responsive to their preferences, needs, and values.

Second, patients must be willing and able to do their part in the trial. Patient activation assesses how well subjects performed their role in the trial.

 Patients must have the knowledge, skills, and motivation to not only manage their health condition but also effectively participate in the trial protocol. Patient-centered medical care, then, is a relational construct in which providers engage patients but subjects also accept responsibility for their role in the care process.  

	Given this definition and implications, we offer a three-step process that trial managers can use to measure patient centricity.

	The first step in developing scientific patient-centricity measurement is to gather patient feedback about the trial. The critical success factor in this activity is to collect the right data. Many managers already gather feedback, for example, on patients’ satisfaction in their trials, and feel like they are measuring patient centricity. But patient centricity is not satisfaction-they are different constructs.

 Collecting unrelated data or undisciplined sampling adds inefficiency, is a waste of money, adds unnecessary complexity to the analysis, and generates biased information that obscures managerial judgment.

	Start your patient feedback program by collecting data on patient engagement (i.e., how responsive the providers were to patients’ needs, values, and preferences) and patients’ perceptions of the quality of the trial. There are established, valid, and

 reliable instruments that clinical teams can use to measure both patient engagement and quality. After reviewing the available instruments,

 we felt that the consultation care measure had the highest face validity for measuring patient engagement in clinical trials, described in Table 1.

	It is also important to include patients’ perceptions of the quality of the study. Since the overall service quality will influence the patient-centricity scores, it is important to know the quality of the trial in order to assess the patient centricity in an unbiased way. We recommend SERVQUAL to measure the quality of the clinical trial.

 The SERVQUAL instrument, shown in Table 2, has been in use for more than 25 years.

 The tool has been tested across multiple industries and has consistently been valid and reliable. Use established, well-accepted instruments like 

SERVQUAL to gather your data whenever possible. Why go through all the work of validating a new instrument when a precision instrument like SERVQUAL is available? 

	Patient engagement and service-quality data would typically be collected at the end of the study in order to understand how variations in patient engagement or quality affects the trial outcomes. Our goal in collecting this data, however, is to improve the quality of a current trial, not just subsequent studies. With that objective in mind, it is more useful to measure patient perceptions early in the trial (while still allowing the patient time to form an assessment), and then periodically throughout the trial. For the first assessment, the patient should have several contacts with the site or provider. After that, the intervals will depend on how often the patient is being seen. Trial participants should not be assessed more than quarterly, and stretching out the intervals will reduce the burden on patients. This approach of multiple assessments will create technical problems (i.e., auto-correlation) for the analysts, but these can be addressed in discussions with your statistical analysts.

	Patient-centricity measurement also includes an evaluation of the trial design. There are no established instruments available for assessing trial design. New assessments will need to be validated to provide scientific measurement. Fortunately, the Patient Centered Outcomes Research Institute (PCORI) has already done the groundwork of identifying all of the topics and issues that should

 be addressed within the trial-design assessment.

 In this section, we operationalize those rubrics into an instrument that can then be validated, as shown in Table 3. The rubric includes four components: planning the study, conducting the study, disseminating the study results, and adherence to the PCORI engagement principles. There are two groups that should be sampled for the trial-design assessments: patients and partners. Partners include family members, caregivers, and patient advocacy organizations.

 While it is permissible to get evaluations from individuals who have multiple roles (e.g., they are a patient in a clinical trial as well as an advocate for the cause), the sample should not rely entirely on partners with multiple roles.

	The planning-the-study assessment evaluates the degree to which patient partners are included in the conception and development of the trial. How much of a voice did patient partners have in identifying the topic, developing the research questions, and selecting the comparators to be studied? How much input did patient partners have in defining the characteristics of study participants? Finally, were the patient partners able to offer advice on how to minimize disruption to patients and incorporate study activities into their stream of activities for ongoing care? This data should be collected as the trial planning is finishing and the study is about to begin. 

	The conducting-the-study section involves measuring the degree to which patient partners participated in carrying out the study. Possible roles for the patients include participating in the drafting and revising trial materials or protocols, assisting with subject recruitment, assisting with data collection, or serving as a patient representative on a data safety monitoring board. This assessment should be timed to be administered as patients are completing the trial.

	The disseminating-the-study-results unit evaluates the degree to which patient partners help identify partner organizations for dissemination, planning dissemination efforts, or even participating in the dissemination (e.g., co-authoring an article or co-presenting at a conference). These data can be collected shortly after the initiation of the dissemination phase, since patients will have formed an impression about their involvement early in dissemination.

	Each of these three areas involve a specific stage of the trial. The fourth instrument assesses adherence to Patient-Centered Outcomes Research (PCOR) Engagement Principles (hereafter, “PCOR Principles”). The PCOR Principles include reciprocal relationships, co-learning, partnerships, trust, transparency, and honesty. Reciprocal relationships refer to the degree to which patient and stakeholder partners are considered key personnel and the degree to which they have decision-making authority in some areas. Co-learning refers to the degree to which patient and stakeholder partners understand the research process and the level to which the research team understands the patient and stakeholder perspectives. Partnership is the degree to which the contributions of the patient and stakeholder partners are valued. Trust, transparency, and honesty means that information is shared readily with the patient and stakeholder partners and they are included in decision-making. This open and honest communication extends from within the research team to the community being studied. The PCOR Principles assessment should be completed whenever any of the stage-specific assessments are administered.

	Patients have to do their part in order for a trial to be considered patient-centric. The degree to which patients are able, willing, and motivated to do their part in a clinical trial is called patient activation.

The first part of patient activation is a self-assessment completed by the study participant. The Patient Activation Scale is a valid and reliable instrument to assess patients’ perceptions of their own 

activation levels (see Table 4). The scale breaks out into four different dimensions: believes role is important, confidence and knowledge to take action, taking action, and staying the course under stress.

The “believes-role-is-important” dimension assesses whether the patient recognizes that they have a role. The “confidence-and-knowledge-to-take-action dimension” measures how able the patient is at taking the initial actions in following the protocol and caring for their health condition. The “taking-action” dimension shifts the perspective from potential ability to the patients’ ability to execute the plan. But patients must also be able to persevere with executing their plan, which is measured by the “staying-the-course-under-stress” section. 

	We recommend that patient activation be measured at the start of the trial as a baseline and then periodically across the duration of the study. The initial activation scores can be used to identify patients with low activation who would benefit from an intervention to improve their activation levels.

 How activation changes over the course of the trial will reflect the impact of the clinical site and

	Self-reports of patient activation may be influenced by social desirability bias.

 To offset this issue, we recommend that providers also assess patients using the Physician Assessment of Patient scale, shown in Table 5.

 We have adapted these items not only for the clinical trial context, but also to facilitate comparison with the Patient Activation scale.

	While there are challenges to measuring patient centricity, we have described a straightforward three-step process that managers can use to begin their patient-centricity measurement programs. It is important to realize that most of the challenges lie in the sampling process. Getting the right instrument to the right person is the challenge, but can be expedited with cloud-based administrative technologies.

	As you begin to gather patient-centricity assessments, it is worth considering how your organization will act on the feedback. If patients are 

taking the time to offer feedback, they will expect a response or some action to their input. Will your organization be able or willing to adapt their clinical trial process to what patients want? Recognize that, at a fundamental level, patient centricity is about power. How much will you let patients dictate what happens in a trial? Obviously it is an issue of balancing power, but this is new territory for the clinical trials industry. 

	Since patient centricity is a dimension of quality-a No. 1 implication of any clinical trial-then patient-centricity measurement should be integrated into an ongoing quality measurement program. Patient centricity should be thought of as an integral component of overall quality and not measured in a vacuum. We have described the scientific way to measure clinical trial quality in previous articles.

	It is important that patient centricity not be assessed with operational metrics. While operational metrics can be “easy data,” they lack validity, which means they lack meaning. To illustrate this problem, we have heard it suggested that the amount of time it takes a site to enter data can be used as a patient-centricity indicator. The rationale is that the more the clinician is focused on their patient, the more inclined they will be to enter the data as soon as the visit is completed. But what if the clinician is spending a tremendous amount of time responding to patient needs, preferences, and values? They are likely to be delayed in entering data while responding to these patient needs. This is the type of problem you get into with operational metrics. It becomes difficult to assign a rational meaning, even though the data is readily available.

	Note that many of the items described here are leading indicators, allowing managers to identify and intervene on impending failures. This means that one of the consequences of this measurement program will be to improve the patient centricity of clinical trials.

	It should be clear from this article that measuring patient centricity is not easy. It takes a lot of work in order to measure patient centricity in a way that meets scientific standards. It is worth considering the potential returns from these patient-centricity measurement investments. Since there is no widespread scientific measurement, we can only speculate about a potential ROI on measuring patient centricity. Since other authors have argued elsewhere about the ethical and patient care benefits,

 we will focus on the other potential returns. 

	The most common reason for denying new drug applications (NDAs) include issues with the selection of trial subjects and the lack of meaningful or relevant endpoints.

 As a result, measuring and then improving the patient centricity of the trial design should enhance the ability to get drug approval. Measuring and improving the patient centricity of the patient care aspects of the trial should enhance site functioning, enhance patient retention, and improve patient recruitment. Finally, patient-centric trials will better illustrate the value of the investigational drug to patients and enhance the ability to get reimbursement on the compound if it reaches the market.

	Patient centricity is an important and necessary development that has the potential to improve the quality, relevance, and value of clinical trials. We are concerned about the perceptions that patient centricity is drifting toward being perceived as a fad. To prevent this from happening, it is important that we begin to measure and manage patient centricity in a valid, reliable, and scientific way. It is critical that we get this right. Patient centricity plays a too-important role in today’s drug development model to allow it to become a fad.

	1. K.A. Getz, “The Transformative Promise of Patient Centric R&D,” 

http://clinicaltrials.pharmaceutical-business-review.com/news/the-transformative-promise-of-patient-centric-rd-070515-4571105 

	2. R. Wright, “How to Build Real Patient Pharmaceutical Companies,” 

http://www.lifescienceleader.com/doc/how-to-build-real-patient-centered-pharmaceutical-companies-0001 

	3. S. Rocchio, “Patient-Centric Clinical Research: A Renaissance in the Making, 

http://www.appliedclinicaltrialsonline.com/patient-centric-clinical-research-renaissance-making 

	4. A fad is defined as a desirable trend characterized by initial enthusiasm and energy over a short period of time that quickly fades away.  Adapted from Merriam-Webster Dictionary at 

http://www.merriam-webster.com/dictionary/fad.

	5. T. Kole, “Patient-Centric Clinical Trials: Fad, Trend, or Future?” 

http://www.almacgroup.com/wp-content/uploads/Patient-Centric-Clinical-Trials-Fad-Trend-or-Future.pdf

	6. P. Ivsen, “The Patient Centricity “Fad” and the Token Patient,” eyeforpharma, July 30, 2014, 

http://social.eyeforpharma.com/clinical/patient-centricity-fad-and-token-patient

	7. For the characteristics of business fads, see J. Hartwick, and D. Miller, “Spotting Management Fads.” Harvard Business Review, 80 (10) 26-27 (2002).

	8. For a review, see M. Furr, Scale Construction and Psychometrics for Social and Personality Psychology. SAGE Publications Ltd, 2011.

	9. Institute of Medicine, Crossing the Quality Chasm, (2001) page 40.

	10. M.J. Howley, and P.M. Malamis, “The Quality of Clinical Trials,” 

http://www.appliedclinicaltrialsonline.com/quality-clinical-trials

	11. M.J. Howley, and P.M. Malamis, “High Performing Study Startups,” 

http://www.appliedclinicaltrialsonline.com/metrics-behind-high-performing-study-startups

	12. M.J. Howley, and P.M. Malamis, “Quality Drivers in Clinical Trial Conduct,” 

http://www.appliedclinicaltrialsonline.com/quality-drivers-clinical-trial-conduct-0

	13. S. James, J. J. Hibbard, T. Agres, R. Lott, and S. Dentzer. “Health Policy Brief: Patient Engagement.” 

	14. J.H. Hibbard, et al. “Development of the Patient Activation Measure (PAM): Conceptualizing and Measuring Activation in Patients and Consumers,” 

	15. J.M. Kupfer and E.U. Bond, “Patient Satisfaction and Patient-Centered Care: Necessary But Not Equal.” 

	16. For a review of patient centeredness instruments, see C. Hudson, M. Fortin, J. Haggerty, , M. Lambert, and E.M. Poitras, “Measuring Patients’ Perceptions of Patient-Centered Care: A Systematic Review of Tools for Family Medicine, 

	17. Despite the name, this assessment provides good measurement of the patient engagement construct. There is a lot of confusion in patient-centricity terminology-both in the managerial and academic sectors.

	18. P. Little, H. Everitt, I. Williamson, G. Warner, et. al. “Observational Study of Effect of Patient Centredness and Positive Approach on Outcomes of General Practice Consultations.” 

	19. A. Parasuraman, V.A. Zeithaml, and L.L. Berry, “SERVQUAL: a Multiple-Item Scale for Measuring Consumer Perceptions of Service Quality.” 

	20. A. Parasuraman, L.L. Berry, and V. A. Zeithaml, “Refinement and Reassessment of The SERVQUAL Scale, 

	21. PCORI Engagement Rubric. patient centricityORI (Patient-Centered Outcomes Research Institute),  

. Published February 4, 2014. Updated June 29, 2015. Page 2.

	22. J. Hibbard, J. Greene, V. Overton, “Patients with Lower Activation Associated with Higher Costs; Delivery Systems Should Know Their Patients’ Scores,” 

	23. R.J. Fisher, and J.E. Katz. “Social-desirability Bias and the Validity of Self-Reported Values,” 

	24. D.H. Thom, S.T. Wong, D. Guzman, A. Wu, et. al. “Physician Trust in the Patient: Development and Validation of a New Measure.” 

	25. M.J. Howley and P.M. Malamis  “Clinical Trial Performance Measures You Can Use (and believe)”, 

http://www.outsourcedpharma.com/doc/clinical-trial-performance-measures-you-can-use-and-believe-0001

	26. MJ Howley and P.M. Malamis (2014) Metrics Malpractice, 

 Online, Accessed June 23, 2015. Available at 

http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/Blogs/How-We-Fall-into-Metrics-Malpractice/ArticleStandard/Article/detail/844223?contextCategoryId=49914

	27. D.M. Berwick, “What ‘Patient-Centered’ Should Mean: Confessions of an Extremist.” 

	28. L.V. Sacks, H.H. Shamsuddin, Y.I. Yasinskaya, K. Bouri, et. al. “Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012.” 

, PA-C, PhD, is Associate Clinical Professor, LeBow College of Business, Drexel University, email: 

, MBA, is CEO, CRO Analytics, LLC, email: 

Feature Article

This three-step process can help managers accurately assess how patient-centric their trials really are.

Preventing Patient Centricity from Becoming a Fad

	In most industries, companies typically gather information and input from their consumers before initiating product development activity. With pharmaceutical development, this is not typically how consumer input guides the process.  

	Historically, pharmaceutical and biotechnology companies have created development plans and designed protocols with little to no direct input

 from patients. Development sponsors have instead relied largely on publications and limited input from intermediaries-usually physicians and other health and research professionals-to define patient needs, endpoints and objectives, and clinically meaningful benefits.

	In other industries, ongoing product development is also informed and refined by beta testing and soft launches. Here, too, active drug development programs receive input but it is limited by the requirements of the study protocol, principles of controlled clinical trials, and regulatory and ethical requirements. That input is also managed and interpreted by intermediaries-the principal investigator (PI) and study staff.

	New research from the Tufts Center for the Study of Drug Development (Tufts CSDD) indicates that this process is inefficient and missing critical opportunities. Despite the depth and volume of data that is gathered during clinical trials, the interpretation and translation of knowledge and insights gained by the PI and study staff is not always reaching the sponsor. 

	My colleague-Marie Smed, a consultant at the Technical University of Denmark-and I looked at the range of insights gathered during clinical research studies and observed inefficiencies and wide variability in the sharing of insights between sponsors and investigators into investigational drug product attributes and clinical practice considerations. And these inefficiencies were generally worse when a CRO was involved.

	Based on extensive literature review and interviews with industry experts and representatives and healthcare practitioners, Tufts CSDD developed a list of primary areas where knowledge is gained about an investigational drug.  Eleven areas were identified across three broad domains:

Investigational drug attributes and effects

		Clinical skills necessary for successful administration of the study drug

		Workforce required to administer study drug

		Patient and professional reaction to study drug positioning (e.g., name)

	Next, 451 global investigators (37% from Western and Eastern Europe; 28% from North America; 24% from South America; and 9% from Asia-Pacific) rated each of the 11 knowledge areas in terms of the level of insight that they obtain and their general ability to share these insights with sponsors and CROs during and after the conduct of the clinical trial.  

	The results of this research showed that for half of the knowledge areas, a relatively high level of insight is gained and shared. But in eight of the 11 knowledge areas there was a significant difference between the level of knowledge and insight gained by the investigator and the level of knowledge and insight shared with the sponsor and CRO. PIs gain more knowledge and insight-in some cases substantially more-than they are able to transfer to the sponsor or CRO.  

	Three of the knowledge areas-all associated with the patient experience domain-received the lowest ratings with respect to the level of insight obtained by investigators. They are not gaining much relative insight or knowledge into patient access and receptivity to product positioning. These areas are typically not central to clinical research study objectives. However, the insights gained from these knowledge areas inform patient choice and behavior.

	Investigators indicated that the investigational drug attributes and effects domain contained the areas where the most knowledge was gained. And this knowledge was the most likely to be shared with research sponsors and CROs. Study drug side effects, dosage levels, concomitant drug interactions, and risk-benefit are among the areas most assessed during clinical trials as required by the study protocol.

	Wide gaps existed between the level of insight gained about the administration of the study drug, the clinical skills necessary and workforce requirements to administer the study drug, and the level of insight shared with sponsors and CROs. 

	Investigator ratings of knowledge shared with CROs followed a similar pattern to that reported of sponsors, but the level of knowledge shared was consistently lower.

	PIs and study staff are obtaining a lot of knowledge about the study drug.  Some of this knowledge, particularly insights into investigational product attributes and their impact, is transferred well to research sponsors.  Knowledge transferred about study drug administration is less efficient. And knowledge about patient experience with the study drug is neither obtained nor transferred well.

	The race to conduct and complete clinical trials may be playing part in limiting knowledge transfer. Study staff and their sponsor and CRO partners are frequently pressed for time as they must meet demanding timelines and as they are compelled to quickly focus on new projects once a given clinical study has ended.  

	Clinical team focus on cycle time optimization and efficiency is likely detracting from opportunities to facilitate the transfer of important knowledge gained during study conduct. These operating conditions are even more pronounced when the CRO is involved. Contract service providers are primarily focusing on successfully executing the clinical study.

	In addition, knowledge associated with patient experience and the adoption and administration of new medical treatments is typically less essential to the objectives of a given clinical 

Despite wealth of data collected, many inefficiencies exist in the site-sponsor transfer of insights from clinical trials.

Applied Clinical Trials-02-01-2016

FDA Looks to New Techology, Policies to Streamline Clinical Research

EMA Adopts New Strategy on Measuring Impact of Pharmacovigilance

Ambition vs. Assessment: The Approval-Reimbursement Divide

How Do You View the Future of Wearables?

Competitive Pressure for First-in-Class Drugs is Intensifying

What Google Can Teach Us About Trial Education, Awareness

Preventing Patient Centricity from Becoming a Fad

Clinical Trial Knowledge Missed, Gained, and Shared

Investigator Characteristics & Patient Recruitment in ALLHAT

Barriers to Trial Recruitment and Possible Solutions

Therapeutic Success or Failure: A Journey, Not Just a Destination

Applied Clinical Trials, February/March 2016 Issue (PDF)