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Practical Strategies to Simplify Patient Centricity: Part 4—Practical and Easier than You Might Think

Posted by Brook White on Tue, Jun 20, 2017 @ 11:00 AM

Ryan Bailey, Senior Clinical ResearcherRyan Bailey, MA is a Senior Clinical Researcher at Rho.  He has over 10 years of experience conducting multicenter asthma research studies, including theInner City Asthma Consortium (ICAC) and the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) project

This is the fourth in a series of blog posts on putting patient-centric principles into practice (view part 1,  part 2, or part 3)

In the previous post, we explored the rationale behind patient centricity and acknowledged the danger we face if we fail to pay heed to the rising tide of patient dissatisfaction with our trials.  In this post, we focus on the more positive and practical aspects of patient centricity, and how a patient-centered approach can improve our work and reduce our costs.

To start, I think it helps to step back and consider why we do what we do.  We are in the business of healing people, of eradicating painful, debilitating, life-taking diseases, and of giving people hope.  How do we do that?  

We rely entirely on the willing and voluntary participation of patients – the real heroes of clinical research.  When patients are in our trials, they put their body on the line, they give their time, they attend visits, they're poked and prodded, and they share blood and tissue and data with us so we can help heal others.  We have an ethical and moral imperative to do right by them.

superhero patient.jpgWhen it comes to ethical protections and patient safety and well-being, we have a number of invaluable guidances that steer our work – the Nuremberg Code, the Declaration of Helsinki, the Belmont Report, Good Clinical Practice, to name a few.  Unfortunately, our familiarity and history working with these seminal documents can sometimes lead to the misleading notion that we've "solved the patient rights stuff."  

However, we cannot be content to rest on our laurels.  We need to consider what lies ahead.  What is next on the continuum of evolving ethical milestones that define our work?  I believe patient centricity is a key aspect.  With patient centricity efforts, we are called to move past our historical approach of saying “we want to do this for patients" to saying “we want to do this with patients."  We change our traditional paradigm of “patient as a participant” to “patient as a partner” in the research space.  We invite patients to contribute their voice to what we're doing, to help us figure out what matters to them, and then we do it.

Of course, this leads to an inevitable question – how do we do that?  Answering the “how” question can seem daunting, especially given the apparent novelty of patient centricity as a movement.  A common impulse is to feel like this is “yet another” set of tasks to burden research teams.  Fortunately, “patient centricity” while relatively new as a term, is not new in concept. 

patient-centricity pyramid

Patient centricity is in our DNA as researchers. Yes, this is an "emerging trend,” but it didn't come out of nowhere.  It's a natural extension of a variety of disciplines and movements we care about – things like adherence, retention, patient advocacy, patient rights, patient-reported outcomes – all of which laid the groundwork for this.  Patient centricity isn’t so much a new trend, as it is a culmination of many different efforts that have been pushing us for years to better accommodate the needs and desires of the patients in our trials.

For example, we already know that patient engagement efforts lead to better recruitment and retention because research on these efforts shows the benefit of understanding and accommodating patient needs.  Likewise, research shows that engaged patients have better adherence and better health outcomes.

There are, rightfully, concerns about adding costs and time to our processes; but the good news is that the investments of patient centricity can prevent many of the “unforeseen” costs that commonly handicap our studies: delayed or insufficient recruitment, high dropout, and poor participant adherence.  What's even better is that research coming out of DIA and the Tufts Center for the Study of Drug Development (available to download here) shows that many of the simplest, most affordable, and lowest time-commitment investments promise some of the best returns.  They found that simple things like involving patient advocacy groups and patient advisory groups in study planning and development, and engaging patients on social media, can have some of the highest impact.

Consider also that patient centricity is a virtuous cycle.  Once you learn what works for a particular group of patients, you can build on that for future research and gain efficiency over time.  Likewise, as research sites and study teams develop reputations for good patient engagement, patients will be more likely to participate in future studies and advocate on your behalf to others in their social groups.

Patient centricity is still evolving as a movement, and you can expect to hear a lot on this topic in the years to come.  For now, the question is one of when to act.  Patient empowerment is happening in healthcare and patient dissatisfaction threatens our industry.  If you’ve experienced the pains of not being patient centric, through slow or stalled recruitment, poor retention, weak adherence, or disappointing patient-reported outcomes, taking a wait-and-see approach is a risky endeavor.  On the other hand, if you are motivated to adapt to the changing patient population, value continuous improvement, and want to see better return on investment, patient engagement is a good place to start.

To get you started, I propose a new acronym (because we don’t have enough in our industry as it is).

AIR – Ask, Inform, Respect

It’s pretty straightforward, but you would be surprised what keeping these principles in mind can do for your relationship with your patients.  To start, ask patients what matters to them and how we can better design trials to meet their needs, and listen to what they say.  Then, make an effort to keep patients as informed as you can throughout the project without threatening study integrity.  Ultimately, respect the patients.  Every one of us is going to be patient at some point in our life. We're only extending to them the same respect and empathy we would hope to get if we were sick, in pain, and anxiously hoping to find a cure that would improve our lives.

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Practical Strategies to Simplify Patient Centricity: Part 3—Why Patient Centricity, Why Now?

Posted by Brook White on Tue, Jun 06, 2017 @ 12:07 PM

Ryan Bailey, Senior Clinical ResearcherRyan Bailey, MA is a Senior Clinical Researcher at Rho.  He has over 10 years of experience conducting multicenter asthma research studies, including the Inner City Asthma Consortium (ICAC) and the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) project

This is the third in a series of blog posts on putting patient-centric principles into practice (view part 1 or part 2)

why patient centricity now?Whether you’ve been tracking the patient centricity movement for years or you’re just becoming aware of this trend, the concept seems to have reached a tipping point recently. Suddenly, everyone is talking about it, every industry conference is hosting sessions on it, and stakeholders throughout the clinical research sphere are starting to ask what patient centricity means for our trials.

Before diving into the practical ramifications of patient centricity, it helps to understand some of the factors responsible for the emergence of this trend. In this post, we examine a few of the driving forces behind patient centricity, and consider consequences for our industry.

You may also notice that this trend goes by many names: patient engagement, patient experience, patient centricity, patient focus, patient advocacy, etc.  While there are nuanced differences to these terms, the underlying principle is the same: we, as researchers, should put concerted effort into understanding, caring about, and addressing the concerns of patients in our trials.

Three trends in particular have been reshaping the healthcare and research landscape when it comes to patient centricity: patient empowerment, personalized medicine, and patient dissatisfaction.

empowering patientsPatient empowerment is being driven by easily accessible information online and an evolving view of the traditional patient-provider relationship. 

Gone are the days when a patient relies solely on the expertise of their physician to understand their disease.  Patients of the Information Age can spend much more time exploring their ailments online than they can in conversations with their provider.  Web-based resources span a wide range of content, from material created and curated by medical experts, to peer-reviewed research, to homeopathic remedies, to patient advocacy sites, to social media information and support groups.  This access to information – even if it is unreliable or misleading – gives patients a greater sense of control over their disease.  As a result, patients are increasingly bringing this information to bear on their treatment and disease management.  

The patient-provider relationship is also evolving.  Increasingly patients view themselves as consumers of healthcare, not passive recipients of it.  Patients can now “shop” for providers, until they find one they like.  Here again, the internet reinforces this trend by allowing patients to search for providers that meet their needs, research and post physician reviews, and seek recommendations from their social network.  This is not necessarily a negative trend.  Many see this as a positive development because it encourages physicians to provide the best possible care and maintain an amiable bedside manner. 

personalized medicineEven as the patient perspective is changing, we also see a growing focus among researchers and medical professionals on providing care for distinct individuals, unique phenotypes, and specialized subgroups.  Commonly dubbed “personalized” or “precision” medicine, this trend places even greater emphasis on understanding the unique manifestation of disease for an individual patient.  Hence, both patients and physicians are pushing medicine to place greater emphasis on the individual patient.

It can be tempting to dismiss these developments as problems for providers rather than researchers, but the implications for our profession are just as important.  Despite our efforts to distinguish clinical trial participation from healthcare, many participants view research teams as part of their care network and trial participation as a facet of their healthcare.  As a result, research participants expect the same level of attention, care, and respect from clinical trial staff as they do from providers.  As patients assume greater power, we have to ask if we are prepared to address the ramifications of these expectations. 

If the rising tide of patient dissatisfaction is any indication, we are not yet doing our part to accommodate patient needs and desires in our trials.  This is evident in the general disdain many hold for the pharmaceutical industry.  A recent Gallup poll found that “of 25 different business sectors, only the federal government is held in lower esteem” than the pharmaceutical industry. 

However, we must avoid reducing this to a mere PR problem.  Individual patients are also voicing their frustration with clinical trials (see the patient statements below).

“Interacting only with interns, nurses, or nurse practitioners and not principle researchers feels like a real blow off. If patients are not important enough to draw the researcher’s attention, why should patients bother going to the effort to participate in research?” – Sarah Kucharski

“The social contract of the randomized controlled trial is imbalanced: patients adhere to arduous protocols, are randomized to placebo, and are blinded to their health status.”Subjects no more: what happens when trial participants realize they hold the power?”  – Paul Wicks, Timothy Vaughan, James Heywood

“The process of getting my mother enrolled into a clinical trial for patients with ALS took a very long time, which was a huge delay. My mother died before she was enrolled…She felt like we were always fighting the FDA and that the FDA was ‘protecting her’ to death.” –Cathy Collet

 This is only a small sample, but it is not hard to find many more quotes like these from patients who are disenchanted with clinical research.  If you’re like me, your first instinct may be to get defensive and respond to these critiques with well-reasoned arguments about the benefits of our work, but that won’t be productive.  A more appropriate response for us is to listen to the sincere concerns our patients are voicing, and respond with empathy.  

Our industry relies entirely on the willingness of patients to participate in our trials.  If you have ever experienced difficulty meeting enrollment, retention, and adherence goals, you can appreciate the threat of a disengaged patient population.  Our response should not be to argue away the frustrations of the dissatisfied, research-averse patients, but to embrace them, learn from them, and adapt. 

This is where patient centricity comes in.  As the term suggests, patient centricity is about putting the patient, and their needs and concerns, at the heart of what we do.  It’s about learning to view patients as partners in the research process, not merely a pathway to a payday.  It’s about listening to their needs and rethinking the way we conduct research. 

The good news is that patient-centered practices need not be difficult, expensive, or onerous.  In fact, some of the simplest and easiest strategies can make a dramatic difference in patient engagement.  We’ll explore some of these, and the positive potential for patient engagement in our next post. 

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Practical Strategies to Simplify Patient Centricity: Part 2—Patient Stories & the Importance of Communication

Posted by Brook White on Tue, May 30, 2017 @ 11:45 AM

Shann Williams, Senior Director OperationsShann Williams has over 10 years of experience managing clinical trials. She is the Director of Operations of the Statistical and Clinical Coordinating Center for the division-wide Consolidated Coordinating Center sponsored by the National Institute of Allergy and Infectious Disease (NIAID). In addition, Shann serves as Rho's Project Management Operational Service Leader, an internal expert sharing project management best practices, processes and training.

This is the second in a series of blog posts on putting patient-centric principles into practice. Click here to view the first post.

Excellent retention practices, such as those shared in the first article in this series, are a great first step but before we implement them and call it a day, we need to ask ourselves, why are we doing this? To keep patients in our study for longer and thereby help ensure study success? Or to put patients’ needs first and thereby help to ensure study success? The difference described may be subtle and but I believe it’s one that can makes all the difference to the patients. Our motivations do tend to guide our actions and communications.
In this post, I’ll share two patient stories that changed the way I thought about my motivation for the work we do in our industry. For me, these highlight the importance of putting patients first in our communications as a first step to putting them first in our clinical trials.

Patient 1

The first patient I describe in my story is me.  My personal struggle with my 2004 diagnosis of lupus and rheumatoid arthritis was compounded by the confusion about what having an autoimmune disease cocktail meant for my body.  Not only was every single joint in my body swollen and painful to the extent that I could not dress myself in the morning without tears, but my rheumatologist was unable to control my symptoms.  The only thing that kept the inflammation down in my joints was a prednisone dosage too high to maintain safely in the long-term.  

Throughout this difficult time when I was learning about autoimmune diseases, my future quality of life, and what it meant to lose the ability to run – something I had always enjoyed – the thing I most appreciated about the health care I received were those providers who listened, who did not rush through to their next appointment, and who offered materials so that I could better understand what was happening to my body: the diagnosis, treatments, and long-term options.

One particular afternoon after a series of frustrating failed call-backs from my doctor and scheduling roadblocks that I continued to run into in order to get a follow-up appointment, I was finally able to speak with a human physician over the phone about additional treatment options. During our brief call, a clinical trial was mentioned. The study was explained hurriedly and almost in an exasperated tone. It was a trial to see whether a product used typically as chemotherapy treatment would work for the severe symptoms I was experiencing in people with my disease.  Unfortunately I never found out if this treatment could have helped me because I flat refused it solely due to the poor communication used when it was described to me. Certainly the company or Government sponsor funding that study would have been horrified to hear how their study was introduced.  Perhaps that care giver was having a bad day.  I’ve often thought that I was only one of many millions and surely my experience was an unfortunate one-off. 

Sadly, however, I don’t believe my story is all that dissimilar from others.  As a matter of fact there is a reason why the Center for Information and Study on Clinical Research Participation (CISCRP) and ICON partnered last year and held the “Inspiring Hope Ideathon” to solicit greater awareness of and participation in research studies—because it’s severely lacking.  

As a matter of fact,according to this study on clinical trial enrollment demand, it would take 1 in 6 people to enroll in a clinical trial to meet enrollment goals for the current studies listed on clinicaltrials.gov.  Why is this the case?  

It would be foolish to assume the challenge lies with communication alone and in the way patients are approached to participate in research.  But, like the old adage says, “how do you eat an elephant?”  It could be a small “bite” in the right direction.   

eating the elephant of patient centricity

Patient 2

Thankfully the story of patient 2 is in stark contrast to my story.  I was waiting with my husband last fall getting ready to get called back for pre-op to have my thyroid removed. We were sitting next to a family in a crowded surgical suite waiting area with their nine-month-old baby girl also waiting for her buzzer to be paged.  Her scheduled surgery was to remove a very rare kidney growth. 

A Study Coordinator sat with them and explained a research study to the mother, father, and grandparents and discussed the potential enrollment of their baby.

The parents were paged and they and the study coordinator went back to pre-op.  Apparently they had signed the consent form because the study coordinator came back to chat with the grandparents.  The thing that struck me was that the study coordinator came back. She sat with them just to see how they were, asked if they needed anything and got them some water, and answered questions about their granddaughter’s disease. The grandparents asked her a slew of questions ranging from “what if it’s cancer?” to specific questions about some of the long-term potential outcomes. The coordinator carefully navigated the questions and often said, “I’m not a doctor but…” and then relayed to them her personal experiences with infant renal dysfunction based on the study.  She spent 20 minutes with them and afterwards as she handed them her card and offered to answer any additional questions they had, and to put them in touch directly with the physician overseeing the study.  As she stood to leave, the grandmother said that she was the first person to care enough to answer their questions and explain what was going on with their granddaughter in months.  The grandmother began to cry and reached to hug the study coordinator. 

Isn’t this why we’re in this industry in the first place?  To help people live healthier, longer lives and increase their quality of life?  Isn’t “bedside manner” and general caring the bare minimum in easing patient burden?  What if all clinical sites vetted and hired competent and caring communicators?  What if we offered specific trainings on how to better approach patients as a requirement for any potential clinical trial recruiter?

Or perhaps a simple change in our motivations and approach could move clinical research participation forward and make the experience better for patients overall. 

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Practical Strategies to Simplify Patient Centricity: Part 1—Overview

Posted by Brook White on Tue, May 16, 2017 @ 11:20 AM

Shann Williams, Senior Director, OperationsShann Williams has over 10 years of experience managing clinical trials. She is the Director of Operations of the Statistical and Clinical Coordinating Center for the division-wide Consolidated Coordinating Center sponsored by the National Institute of Allergy and Infectious Disease (NIAID). In addition, Shann serves as Rho's Project Management Operational Service Leader, an internal expert sharing project management best practices, processes and training.

This is the first in a series of blog posts on putting patient-centric principles into practice.

patient-centric.jpgThe term patient centricity is fraught with uncertainty for many.  This term carries the nuances of widely varying practical application methods as well as theoretical disagreements from stakeholders in our industry. For example, an article in Applied Clinical Trials entitled FDA and Industry Share Perspectives on Patient Centricity contrasted the biopharmaceutical industry and the FDA’s perspectives on patient centricity and concluded that industry thinks patient centricity is patient engagement, whereas the FDA is focused primarily on developing clinically meaningful outcomes to patients.

Although it is understandable that we would be intimidated by the lack of regulatory guidance and the uncertainties of taking on risks in any relatively new area, I would argue that this isn’t rocket science. Some of the same practices we have known about for years that make for successful studies can be implemented to demystify patient centricity and provide a starting place. 

Let’s take the well-known adage: How do you eat an elephant?  One bite at a time, right? Specifically, how do we eat the elephant of patient centricity?  We can employ simple, actionable, “bite-sized” strategies that will move us closer to a more patient centric approach.


I’m not planning to cover the entire elephant, but rather will focus on what we’ve learned that has proven successful. For additional information on “the whole elephant,” I encourage you to read the findings from this DIA/Tufts study. 

Two high-level concepts that we’ve learned from years of clinical and community-based research have positive impacts on studies and are bite-sized portions toward patient centricity: easing patient burden and effective communication.  And, as the DIA/Tufts study reported, these are well in line with what they called “study volunteer ease” which was found to have the biggest bang for a relatively small investment.

Easing Patient Burden

Implementing the same successful practices we’ve used to achieve high retention rates is a first step toward reducing patient burden and allowing for a more patient focused approach.

High participant retention is important for any clinical research trial. It is critical to our ability to reach power for study analysis and is an indicator of overall study success. Those of you reading this post are likely from about the same socio-economic demographic with similar life circumstances: a busy career and a busy life outside of work.  How many of us would make the time to participate in clinical trials even when our careers hinge on their success? Very few of us, it seems, since it would currently take 1:6 Americans to participate in clinical trials to fulfill the enrollment goals for the studies currently listed on Clinicaltrials.gov.

Why is participation so low? Besides the risks and the poor perception of our industry, it is likely also because we know the burden and inconvenience is too great. Patients choose to participate in studies because the benefit of their participation outweighs their perceived risk, burden, and general inconvenience. Some patients are being altruistic while others are hoping their participation will improve their health. We can help to change the perception of clinical trials by making them less burdensome for patients overall.child-and-doctor.jpg

The Urban Environment and Childhood Asthma (URECA) study is an observational birth cohort study currently in its 12th year. It was funded out of the National Institutes of Allergy and Infectious Disease. URECA currently has 606 total patients enrolled. In its first two years it had 89% retention rate and  461 of the 606 original patients are still enrolled (76% retention) 12 years into the study. That high retention is attributable to several patient-focused practices described in detail below.  Patient focused practices start by looking at the study from the patient’s point of view. 

For example, we cannot expect patients to accommodate our schedules. We have to think about the logistics of what we’re asking them to do from their perspective.  Do they need to take off work? Will they need to miss school?  Are they going to have to deal with the complexities and stress of hospital and clinic parking decks?  How many of us ever complete surveys received in the mail actually return them? How many of us are annoyed by the constant barrage of emails in our inboxes?  Are we more likely to respond to a text message or return a call left on our voice mail?  

If we don’t think through these very simple things carefully, we are setting ourselves for enrollment challenges, the potential of multiple (and costly) protocol amendments, and we won’t be any closer to relieving the burden of clinical trial participation for our patients. Even if a protocol is designed with patient outcomes in mind, without implementing some basic principles, we’ve failed to take the patient into consideration.

These were the 8 patient-focused practices employed in the URECA study and discussed in detail in our publication in Clinical Trials from 2010

  • Call hours
    • Consider conducting any reminder phone calls, follow-up questionnaires or recruitment and screening calls after regular business hours when patients are more likely to be available. 
  • Employ culturally competent staff
    • Employing culturally competent staff that speak the patient’s native language, understand the nuisances of that specific population, and identify with challenges and considerations within that specific demographic and geographic location is imperative to putting patients first.
  • Flexible visit scheduling
    • Along the same lines as conducting calls after hours, is the clinic/site open on Saturdays? Consider scheduling changes that will allow patients to come in the early morning or evenings to avoid missing work and school.
  • Provide reimbursements for transportation and parking (no brainer!)
  • Host retention events
    • This is an example of something that worked for this specific population that may not work for others and points back to really knowing your population via hiring competent staff.  Since these were mothers and their young children, these events brought a sense of community.  Patients got to know other mothers and children that were in the same study and were able to create relationships and deepen relationships with study staff. 
  • Offering home visits
    • The success of this study hinged on our ability to meet the needs of this population. Young mothers with asthma who have babies with respiratory infections do not want to brave the winter in Boston to call a taxi to take them across town so that they can have a nasal lavage performed. This is not without risk though, and an option like this has additional implications that must be considered carefully.
  • Cell phone or texting reimbursements
    • This is especially important for those families who buy minutes. 
  • Distributing quarterly newsletters 
    • This is an easy way to make families aware of study status. The one from last December offered an update on the study retention rates and included indoor activities – making snowman cookies, connect-the-dots snowman for the children, and tips for staying safe in cold weather. These are more than just visit reminders or asthma educational materials, they are geared toward ensuring the patients feel engaged in the study. 

These practices take careful pre-planning, but by incorporating just one principle based on the time, schedule, and budget for each study, we can move forward in the right direction toward putting our patients first.

Look for the second post in this series which will share some specific patient stories that highlight the importance of our second patient centric principle: effective communication.

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Key Take-aways from ACRP 2017

Posted by Brook White on Fri, May 05, 2017 @ 11:15 AM

key take aways from ACRPThis week I attended the 2017 ACRP Annual Meeting in Seattle.  Here are some of the key trends, themes, and ideas that I took away.  There were obviously far more sessions than any one person could attend, so I’m sure there are pieces I missed.  If you attended, please feel free to add your thoughts to the comments below.

Core Competency Framework for Clinical Study Monitoring

framework for clinical study monitoringOne of the biggest announcements of the conference was that the Workforce Development Task Force and Steering Committee released a core competency framework for clinical study monitoring.  The goal of the framework is to standardize professional expectations for individuals involved in clinical study monitoring.  The framework is intended to define competency requirements for individuals involved in study monitoring regardless of experience level across eight domains—clinical operations/GCPs, communication and teamwork, data management and informatics, ethical and participant safety concerns, leadership and professionalism, medicines development and regulation, scientific concepts and research design, and study and site management. The core competency framework can be downloaded here.

ACRP Announces New Certification Program

certified professionalACRP announced a new certification program, ACRP-CP (certified professional).  The new certification provides a non-role specific alternative to the existing role specific Certified Clinical Research Associate (CCRA), Certified Clinical Research Coordinator (CCRC), and Certified Principal Investigator (CPI) certifications.  The new credential seeks to formally recognize individuals with the skills, knowledge, and abilities to perform ethical and responsible clinical research regardless of their specific role.  The first certification exam will be held this Fall.

Transparency and Flexibility from FDA

regulatory transparencyThe first session on Saturday was a panel discussion with four speakers from FDA—three from the Center of Drug Evaluation and Research (CDER) Office of Scientific Investigations (OSI), and one from CDER Office of Integrity and Surveillance. As I commented following ACRP and DIA last year, FDA seems to be making a concerted effort to be accessible, transparent, and flexible in communicating with professionals involved in research. As a matter of fact, one of their stated strategic goals was stakeholder engagement (the others were user fee requirements, responsible stewardship, global context, and subject rights, safety, and welfare). They also stated that in places where existing guidance and precedence doesn’t exist and is needed to move research forward, drug developers should come to them with questions rather than waiting for formal guidance. In addition to the panel discussion, the three speakers who attended in person stuck around and held office hours Saturday and Sunday to talk to conference participants.

The panel addressed several questions that related to themes seen more broadly at the conference.

State of the Industry

Day 2 opened with a panel discussion on the state of the industry featuring ACRP President Jim Kremidas, Ken Getz from Tufts University Center for the Study of Drug Development (CSDD), Elisa Cascade, President of Data Solutions, Leanne Madre Director of Strategy for the Clinical Trials Transformation Initiative (CTTI) at Duke University, and ACRP’s Workforce Innovation Officer, Terri Hinkley.  The panel focused their discussion on four broad forces impacting clinical trials:

  • Consolidation
  • Datafication
  • Integration
  • Uberization

Organizations involved in clinical trials are consolidating across the continuum. We are seeing both consolidation for economies of scale—CRO mergers and acquisitions, sites fusing into site networks—and vertical consolidation where organizations are increasing their capabilities—CROs buying site networks and central labs. It remains to be seen how this will impact clinical trials as a whole.

Datafication is the increased ability to gather and access ever increasing amounts of both structured and unstructured data that can be used in clinical research. The average phase III study now collected nearly 1 million data points. Additionally, we are seeing more data that is collected to drive payer and prescriber behavior rather than just to demonstrate safety and efficacy.

Integration refers to the efforts to better connect people, processes and technology. There are a number of national level initiatives to improve clinical research like CTTI, TransCelerate, and MDIC, a device and diagnostic initiative. These organizations have potential to move some agreed upon concepts from idea to reality. For example, both the NIH and the 21st Century Cures Act call for use of central IRBs, and CTTI is working on tools that can help make that happen. When it comes to technology, the perception is that the industry is suffering from “death by pilot.” People and organizations are willing to try lots of new technology, but consistent industry wide adoption is incredibly slow and lacking in standardization. Even EDC, which is hardly new or innovative at this point, is only used by 50% of studies globally. Common complaints and barriers include lack of consolidated platforms and the need to use different software and different login information for each study.

Uberization is moving research into healthcare in a way that works best for patients. There are greater pressures than ever to make research patient friendly rather than convenient for sites, PIs, CROs, and sponsors. Without patients, studies won’t happen. In this talk as well as others, there is a sense that patient centric practices aren’t just the right thing to do, they are necessary to succeed in research.

Finally, the panel identified key drivers for change over the next 3-5 years:

  • Collaboration: Industry and CROs working together allow for standardization and process improvement.
  • Regulatory willingness to try new things.
  • The internet of things—devices in our lives provide access to information in new and objective ways.
  • Technology that is easy enough to use that training isn’t necessary.

Innovating Clinical Trials with Mobile Technology

mobile technology for clinical trialsDay 3 featured a panel discussion on the CTTI mobile technology initiative.  The initiative contains four working groups addressing:

  • Mobile devices
  • Novel endpoints
  • Stakeholder perceptions
  • Legal and regulatory issues

The goal is to provide evidence-based recommendations that allow an increased number of clinical trials to leverage mobile technologies.

One question they addressed upfront was the benefit of using mobile given the additional effort needed, and they provided four key answers:

  • Potential reduction of burden on trial participants
  • Increased patient access to clinical trials
  • Availability of objective data
  • Ubiquity of devices

The initiative has focused on studies conducted in the US, although they recognize it is a global issue. The stakeholder perception group is addressing concerns about security as well as concerns about losing the time and attention of the doctor providing care. The novel endpoints group is looking at new endpoints that are now possible to assess as well as existing endpoints that can be assessed more easily or more accurately than is possible with non-mobile technologies. The mobile devices group is looking at devices that can address existing challenges, data attribution concerns, and the identification of the difference between real needs to address research questions versus data fishing expeditions. The legal and regulatory group has its hands full with a variety of issues—understanding FDA’s willingness to accept mobile technologies, addressing privacy and confidentiality concerns, telemedicine challenges, dealing with IRBs, shipping issues, and reimbursement.

Finally, people were invited to engage in the process by signing up for updates or to participating in evidence gathering (ctti@mc.duke.edu).

eHRs and Study Oversight

A significant concern expressed by auditors and monitors alike in a number of sessions is that site and institutions implementation of eHR systems do not provide adequate mechanisms for monitors and auditors to provide oversight.  In some cases they are being provided with copies or printouts that are illegible rather than provided with direct access to eHR systems.  In other cases, they are provided with access to eHR systems, but important information is sequestered.  A common complaint is that sensitive records like those associated with mental illness, sexually transmitted infections, and substance abuse is are not being made available even when those records are relevant to the research and may reflect AEs.  In one example, it came to light that a subject had attempted suicide while on an investigational product, but it was not initially reported as an AE and the study monitor was not allowed access to the record.  With the increased use of eHRs in healthcare settings, this is not likely an issue to go away soon.


Not surprisingly, many if not most sessions touched on the impact of the ICH E6 revisions and their impact to studies.  Additionally, there was a two part session held specifically to review the revisions and discuss their impact.  This is an extensive topic that is well discussed elsewhere, so I won’t go into detail here. 

Importance of Conducting Ethical Research

While this isn’t new, ACRP continues to press the importance of conducting clinical research in ethical ways and expecting professionals involved in research to understand what that means.  There were a number of excellent sessions on research misconduct and the relationship to public trust, ethical considerations in pediatric research, and recognizing vulnerable patients and patient populations.

Business Intelligence and Study Management

As the global volume of available data sources increases exponentially, those in clinical research are becoming more aware of the benefits of transforming these raw data sources into useful information for analysis purposes. The ability to effectively utilize the data we currently have depends on the thoughtful construction of metrics and key performance indicators (KPIs). The simple establishment of these types of measures must develop an even balance; a study can have too many metrics (which confuse the purpose), too few metrics (which offer weak benefit and minimal impact), or a focus that is too broad where one area grows strong at the expense of another. Other common pitfalls are underestimations of the time and effort required to combine various data sources, imbalances between metrics and action, and metrics that are developed for the sake of metrics. The development and use of these metrics and KPIs requires a cycle of continuous improvement: High-impact metrics must be identified and developed, accurate data gathered, and the lessons learned converted to actionable strategies and reassessed continually to correctly estimate our return on investment.

Thanks to Derek Lawrence for contributing to this article.

Not Just Tiny Humans: Considerations for Conducting Pediatric Clinical Trials

Posted by Brook White on Tue, Apr 25, 2017 @ 09:43 AM

Jamie Arnott, BSN, RN--Project DirectorCaitlin Hirschman, RN, BSN--Clinical Team LeadProject Director Jamie Arnott, RN, BSN and Clinical Team Lead Caitlin Hirschman, RN, BSN have extensive experience in pediatric clinical research including recent studies in rare diseases and diseases with a seasonal component.

When it comes to the conduct of pediatric clinical trials, there are number of things you need to consider in order to ensure the successful conduct of a study. While we can’t predict the outcome, planning ahead for appropriate site conducting clinical studies in pediatric patient populationsand subject selection will take you one step closer. From study design to logistics to recruitment, there are real differences between studies conducted in pediatric populations and studies conducted in adult populations.

Patient Recruitment

While patient recruitment can be challenging in any study, there are additional challenges to recruiting pediatric patients.  Parents may be more risk averse to giving an unproven therapy to their child than they would towards receiving it themselves.  To improve the chances of successfully enrolling a study, it is important to consider potential motivators for participation:

  • Therapeutic benefit: If you are working on a therapy for a rare disease or for an indication where there is no approved or effective product, parents may be motivated by the opportunity to receive treatment that could improve their child’s condition even if it isn’t proven and if there is a chance they will receive placebo.  When there is an approved effective treatment available parents are likely to be reluctant to sign their child up when they may receive placebo, receive a treatment whose effectiveness is unknown, or receive a treatment with unknown side effects and safety issues.
  • Financial incentives: Many studies offer financial incentives to participants, and this can be a motivating factor for some parents.  Additionally, patients may receive study related medications, assessments, or more routine care that could be cost prohibitive otherwise.
  • Research benefit: Particularly for studies in rare disease or orphan indications, parents may see the benefit in research that provides a better understanding of the disease or the prospect of better treatment options in the future even if their child does not receive a direct benefit in participation.

Understanding what motivates parents to allow their child to participate in a clinical research study will help you to determine how to advertise and recruit for your study.  Some recruitment tactics (with appropriate ethics committee approval) to consider include:

  • Directly reaching out to parents by calling or through email.
  • Advertising at family events or locations where children and parents are likely to attend.
  • Reaching out to healthcare providers who may be the patients’ first point of contact even if they are not the location where the study will be conducted.  For example, if you conduct a study where the sites and investigators are typically at specialty practices, you may still want to recruit through primary care providers.
  • Consider referral processes for these types of sites to ensure patients are considered in a timely manner, based on their indication/treatment needs.

Patient Retention

using electronic devices in pediatric clinical studiesGetting pediatric patients enrolled in a study is great, but it is just as important to make sure most patients are completing the study.  There are a number of factors that make this more difficult in a pediatric study:

  • Multiple schedules to coordinate: Each study visit requires both the parent and child to be available.  Studies with numerous visits can become a significant hassle for parents, which can lead to discontinuations.  Making sure that every visit is necessary and being as accommodating as possible with scheduling, such as including flexible visit windows can mitigate this risk. (Remember: Most of the parents still have to work and kids attend school).
  • Parents don’t see the therapeutic benefit: If parents come to believe that their child is receiving placebo or that the treatment is ineffective, they may withdraw their child from the study. Providing clear information about what the trial is evaluating and encouraging frequent communication will help facilitate the parent voicing any concerns.
  • Discomfort of participation: No one likes long doctor visits or being stuck repeatedly with a needle, but these discomforts are even harder on pediatric patients and their parents.  Evaluate each assessment carefully during protocol development (even ones like blood pressure and temperature monitoring) to reduce the overall burden to the patient.

What can be done to improve retention? Encourage investigators to talk with parents about the importance of completing the study.  Consider what incentives may be appropriate to improve retention and work within the limitations of what the IRB will allow based on your study. Cash incentives may be effective with older patients and with parents.  In some cases, we’ve seen where study information or assessments are loaded on a device like a tablet that the patient may get to keep at the end of the study.  Treats or fun activities such as coloring books or video games to play at study visits can be good incentives for younger patients.  Keep in mind that there may be limitations on what you can provide as incentives.  All incentives will require IRB approval. Finally, keep visits as short as possible, limit blood draws and invasive procedures, that every procedure and assessment is truly necessary to determine the safety or efficacy of the investigational product.

Informed Consent

Pediatric studies introduce several challenges when it comes to informed consent:

  • Typically, if patients are at least 7 years old, in addition to parental consent you will need assent from the patient.  Assent documents will need to be written at an appropriate reading level.
  • In pediatric studies, parents are likely to want to know which treatment their child received and the outcome of the study after the study is complete.  Information on whether this will be made available needs to be included in the consent document.
  • You will need to decide whether consent is required from both parents.  If not, and the parents are divorced, can either parent make the decision?  If you do need consent from both parents, this can be an additional hurdle to enrollment.

Other Considerations

In our experience there are a number of other considerations that require proper planning to ensure study success:

  • Pregnancy tests: In many cases, pregnancy tests will be needed for female patients.  Depending on the age of the child and the view of the parents, this may be a hurdle.  In many cases, these tests are required at an earlier age than parents anticipate—typically as young as 9 years old.  Parents and patients do need to be informed if the test is being done.
  • Objective outcomes: For studies with young patients, objective outcomes are highly preferable to outcomes that rely on the reporting of the patient or parent.  If patient-reported scales are used, staff will need to be trained to get answers from the patient rather than the parent.
  • Sibling bias: The protocol will need to specify whether siblings can participate in the study.  Allowing siblings to participate may be helpful for enrollment, but it can also introduce bias into the results and potentially create a risk if home treatment is required.  There is a risk that if siblings are in different treatment arms, the treatments could be mixed up, while at home,  resulting in subjects receiving the incorrect treatment.
  • Dosing during school hours: If the protocol requires dosing during school hours, this may require extra paperwork/legwork on the part of the parent to gather supportive information allowing the school staff to give this investigational product (IP).  Many schools will not give IP to students and may not allow students to retain IP even if it is self-administered.
  • Missed school: Frequent visits during the school day or overnight visits may cause absenteeism issues for school-aged children.
  • Continuation: Consider whether participants will be able to continue receiving the product after the study, for example, through an open label extension of the study.  Even for a Phase III study, it may be several years before a product receives marketing approval.

Conducting clinical research in pediatric populations does introduce a unique set of challenges.  With proper planning, however, many of these challenges can be avoided or mitigated.

Download 5 Lessons Learned Conducting ADHD Trials

FDA Guidance on Non-Inferiority Clinical Trials to Establish Effectiveness

Posted by Brook White on Thu, Apr 20, 2017 @ 11:42 AM

Heather Kopetskie, Senior BiostatisticianHeather Kopetskie, MS, is a Senior Biostatistician at Rho. She has over 10 years of experience in statistical planning, analysis, and reporting for Phase 1, 2 and 3 clinical trials and observational studies. Her research experience includes over 8 years focusing on solid organ and cell transplantation through work on the Immune Tolerance Network (ITN) and Clinical Trials in Organ Transplantation (CTOT) project.  In addition, Heather serves as Rho’s biostatistics operational service leader, an internal expert sharing biostatistical industry trends, best practices, processes and training.

In November 2016, the FDA released final guidance  on Non-Inferiority Clinical Trials to Establish Effectiveness providing researchers guidance on when to use non-inferiority trials to demonstrate effectiveness along with how to choose the non-inferiority margin, test the non-inferiority hypothesis, and provide interpretable results. The guidance does not provide recommendations for how to evaluate the safety of a drug using a non-inferiority trial design. This article provides background on a non-inferiority trial design along with assumptions and advantages and disadvantages of the trial design.


A non-inferiority trial is used to demonstrate a test drug is not clinically worse than an active treatment (active control) by more than a pre-specified margin (non-inferiority margin). There is no placebo arm in non-inferiority trials. A non-inferiority trial design is chosen when using a placebo arm would not be ethical because an available treatment provides an important benefit, especially for irreversible conditions (e.g. death). Without a placebo arm to compare either the test or active control against it is important to determine that the active control had its expected effect in the non-inferiority trial. If the active control had no effect in the non-inferiority trial it would not provide evidence that the test drug was effective.
The table below compares superiority with non-inferiority trials with respect to the objective and hypotheses. The effect of the test drug is ‘T’ and the effect of the active control is ‘C’. The difference tested during analyses is C – T.

  Superiority Trial Non-inferiority Trial
Objective To determine if one intervention is superior to another To determine if a test drug is not inferior to an active control intervention, by a preset margin
Null Hypothesis No difference between the two interventions The test drug (T) is inferior to the active control (C) by some margin (M) or more (C – T >= M).
Alternative Hypothesis One intervention is superior to the other The test drug (T) is inferior to the active control (C) by less than M (C-T < M)


Selecting a non-inferiority margin in a trial is challenging but also critical to a successful trial. The largest possible choice for the non-inferiority margin is the entire known effect of the active control compared to placebo, called M1. However, doing this, would lead to a finding that the test drug has an effect greater than 0. More generally, the non-inferiority margin is set to some portion of M1, called M¬2, to preserve some effect of the control drug, based on clinical judgment. For example, if a superiority trial of the active control demonstrated to be 15% better than placebo, a clinician may set the non-inferiority margin to be 9% (M1=15%, M2=9%). This would be 6% worse than the active treatment, but still 9% better than placebo.

Multiple results are possible in a non-inferiority trial as explained in the graphic below. The point estimate is indicated by the square and is the measure of C – T; the bars represent a 95% confidence interval; and ∆ is the non-inferiority margin.

non-inferiority drug trial, interpretation of results

  1. Point estimate favors test drug and both superiority and non-inferiority are demonstrated.
  2. Point estimate is 0 suggesting equal effect of active control and active treatment. The upper bound of the 95% confidence interval is below the non-inferiority margin so non-inferiority is demonstrated.
  3. The point estimate favors the active control. The upper bound of the 95% confidence interval is less than the non-inferiority margin, demonstrating non-inferiority. However, the point estimate is above zero indicating that active treatment is not as good as the active control (C – T > 0), even while meeting the non-inferiority standard.
  4. Point estimate is 0 suggesting equal effect, but the upper bound of the 95% confidence interval is greater than the non-inferiority margin so non-inferiority is not demonstrated.
  5. Point estimate favors the active control and the entire confidence interval is above the non-inferiority margin so inferiority is demonstrated.

Non-inferiority Margin

The selection of the non-inferiority margin is critical in designing a non-inferiority trial and the majority of the FDA guidance focuses on this. The non-inferiority margin is selected by reviewing historical trials of the active control. The active control must be a well-established intervention with at least one superiority trial establishing benefit over placebo. If approval of the active control was based on a single study (not unusual in the setting of risk reduction of major events such as death, stroke, and heart attack), changes in practice should be evaluated. Using the lower bound of the 95% confidence interval provides a conservative estimate of the active control effect. If multiple historical trials exist one of the assumptions of the non-inferiority trial is consistency of the effect between the historical studies and the non-inferiority trial. Therefore, if consistency isn’t present between the historical studies this can lead to problems in estimating the active control effect. Inconsistency can also sometimes lead researchers away from performing a non-inferiority trial, especially if a historical trial did not demonstrate an effect. In situations with multiple historical trials, careful review of all study results and a robust meta-analysis are crucial to selecting an appropriate non-inferiority margin.

Assay Sensitivity and Constancy Assumption

Assay sensitivity is essential to non-inferiority trials as it demonstrates that had the study included a placebo arm, the active control – placebo difference would have been at least M1. The guidance outlines three considerations when determining if a trial has assay sensitivity.

  1. Historical evidence of sensitivity to drug effects
  2. The similarity of the new non-inferiority trial to the historical trials (the constancy assumption)
  3. The quality of the new trial (ruling out defects that would tend to minimize differences between treatments)

The constancy assumption in #2 above is that the non-inferiority study is sufficiently similar to the past studies with respect to the following design features.

  • The characteristics of the patient population
  • Important concomitant medications
  • Definitions and ascertainment of study endpoints
  • Dose of active control
  • Entry criteria
  • Analytic approaches

The presence of constancy is important to evaluate. For example, if a disease definition has changed over time or the methodology used in the historical trial is outdated the constancy assumption may be violated and the use of a non-inferiority design may not be appropriate. If all the design features are similar except the patient characteristics the estimate of the size of the control effect can be adjusted if the effect size is known in the patient sub-groups.

Benefits of non-inferiority trials

  • A non-inferiority trial is useful when a placebo controlled trial is not appropriate.
  • A non-inferiority trial may also test for superiority without concern about inflating the Type I error rate with care planning of the order in which hypothesis are tested. The reverse is not true; a superiority trial cannot claim non-inferiority.

Disadvantages of non-inferiority trials

  • Must be able to demonstrate assay sensitivity and the constancy assumption hold. This is especially difficult when medical practice has changed since the superiority trial (e.g. the active control is always used with additional drugs currently).
  • When the active treatment is not well established or historical trials have shown inconsistent results choosing a non-inferiority margin proves to be difficult.
  • If the treatment effect of the active control is small, the sample size required for a non-inferiority study may not be feasible
Download: Understanding Dose Finding Studies

Six Things to Consider When Selecting a CRO for your next Pain Trial

Posted by Brook White on Thu, Mar 09, 2017 @ 01:35 PM

Emily Cantrell, Senior Director OperationsEmily Cantrell, Senior Director Operations, has ten years of experience managing Phase 1-3 trials and utilizes her experience and customer service background to ensure seamless communication throughout the life of a trial. Her focus has been in pain management, including successful management of six full-service Phase 2 and 3 pain trials from study start through NDA submission. 

Ben Vaughn, Principal Statistical ScientistBen Vaughn,Principal Statistical Scientist, has participated in over 25 marketing applications and is an expert on CDISC implementation and standards. His work has included coproducing the ISS/ISE for multiple analgesic products; and statistical consultation, display generation and submission work for several chronic and acute pain products. In the past three years, he has supported five opioid sponsors at DAAAP advisory committee meetings, both back room and bullpen.

Pain trials are unique among clinical trials, and it is important to select a clinical research partner that understands and embraces the many differences. There are several key factors to consider when choosing a CRO to work with on your next pain trial.

1. Enrollment

In any pain study, enrollment may present a challenge. For example, in acute pain model studies, sites tend to enroll quickly and sponsors can find themselves in an over-enrollment situation. Some overage can be helpful to account for subjects withdrawing early from the study, but too much overage can significantly impact exceed the trial’s budget. Sponsors must work with the CRO to set a reasonable cap on the overall number of subjects enrolled to minimize overages while allowing sites to continue to enroll without undue restrictions. For example, for a phase III bunionectomy study, we were able to complete enrollment seven weeks early while managing the enrollment cap by using experienced CRAs and maintaining strong relationships with high performing sites.

Chronic pain studies present the opposite challenge. Enrollment is usually much slopain clinical trial enrollmentwer than what sponsors hope for, as chronic pain studies can be a tough sell for subjects. Why enter a trial if your current medication is already working and risk receiving a placebo, a rescue medication offering little analgesic control, or an experimental new drug which may or may not work? Naturally, this presents challenges when meeting predetermined time
lines. During a recent osteoarthritis study, we were able to complete enrollment early by expanding advertising programs across all sites, closing underperforming sites while increasing enrollment caps at high enrolling sites, and continuing to run advertisements throughout the entire enrollment period.

In both situations, transparency with your CRO is key. Understanding a realistic budget and timeline will help keep your trial running smoothly. Your CRO should be able to provide data to support budget and timeline projections. At times, sponsors may be reluctant to approve advertising expenses upfront. For one particular sponsor, we were able to provide them with a comparison of the advertising costs versus the cost of extending the timeline if enrollment targets weren’t met. This comparison encouraged them to move forward with early advertising, and, as a result, their enrollment target was met.

During site identification for another study, it became apparent to us that some of the sites provided by the sponsor were likely to enroll few, if any, patients. We recommended dropping these sites in favor of higher enrolling sites or adding a couple of additional sites to make sure that enrollment rates met their expectations. The sponsor declined because the investigators at those sites were key opinion leaders (KOLs) and they didn’t want the additional expense of adding more sites. In the end, it took an additional 2 months to complete enrollment. Sometimes it is a choice between paying more upfront to reduce the risks of slow and costly enrollment period extensions.

Another obstacle we see is that some sponsors estimate site budgets too low rather than market value for site payments. While we do our best to negotiate the best site agreements we can on behalf of sponsors, unreasonable budget expectations can lead to a study not being able to initiate enough (or the right) sites. The costs in timeline extensions often exceed the costs of offering market-based site payments upfront. Your CRO should be able to provide you with market-based estimates for site payments based on your study design and their experience in similar studies.

2. Subject Reported Data

Pain is not usually a visible condition. A health care professional cannot look at a subject and objectively determine how much pain that person is in. The only way to gather data during pain trials is to ask the subjects to report the information themselves. Any time subjects must provide their own data from a trial, site staff must be educated to work with subjects to better standardize subjective data collection. Similarly, subjects must receive training from site staff on how to report the information, whether electronically or on paper.

If an abnormal value entered by the subject is discovered in your data, the site cannot go back and request a clarification. For example, a subject reporting only to one extreme – all 10s say, or all 1s – is not considered clean data. In an acute pain trial, it would need to be determined how to best represent these outlier data. In a chronic trial, the study team and CRAs must revisit the site for retraining purposes.

3. Data Monitoring

clinical trial data monitoringBecause there is generally a great volume of data collected in any pain trial, it is important that a CRO monitor these data regularly. This requires a keen eye and can be quite time consuming, particularly in acute pain trials because subjects may leave the clinic before data is available to the study team. However, frequent visits to a site can help catch errors and irregularities before they become a major concern. The study team should look for outliers in the data to identify sites that may need more frequent monitoring visits or additional training for site staff. It is also important to have an experienced CRA capable of monitoring the large amount of data while visiting sites.

To manage this, many sponsors require that CRAs for pain trials have a certain level of experience. As a result, sponsors should be mindful to ensure their selected CRO can meet these expectations for staffing purposes.

4. Drug Preparation

For many pain trials, the investigational product (IP) or rescue medication may be a controlled substance scheduled by the DEA. CROs must be familiar with both DEA and state licensing requirements and forms and must also have an understanding of how to ship, move, and monitor scheduled drugs.

5. Diversion & Misuse

drug diversion and misuseDiversion and misuse of medications can be an issue in pain trials, particularly for chronic subjects. If IP counts appear incorrect, sponsors need to determine if it was a mistake or something more. The CRAs should work closely with sites to ensure IP accountability is performed on a very regular basis.

Because pain, is not necessarily a visible condition, site staff need to be diligent in recognizing suspicious behavior and detecting drug-seeking individuals. This is another area where a well-trained site can make all the difference. It is imperative to consider these points during the site selection process.

6. FDA Approval

FDA approvalA final point to consider when selecting your CRO is the experience of the team in supporting submissions for Food and Drug Administration (FDA) approval. DEA-scheduled drug trials not only need to demonstrate safety and efficacy, but must also address the human abuse liability/potential (HAL/HAP). Additionally, FDA’s Division of Anesthesia, Analgesia and Addiction Products (DAAAP) has been quick to enforce the recommendations of a 2010 FDA position paper on missing data, so sponsors must be extremely precise in their treatment of missing data or risk rejection.

Ultimately, there are many considerations a sponsor must make when selecting a CRO for a pain trial. Trained and experienced project staff are key in keeping trials moving forward with ease, detecting potential issues and monitoring vast quantities of data quickly. Any CRO seeking work on pain trials should also be prepared to demonstrate positive relationships with study sites, which can help ensure good subject recruitment and produce clean data.

Free Ebook: Analgesia Protocols

An Interactive Suite of Data Visualizations for Safety Monitoring

Posted by Brook White on Thu, Feb 23, 2017 @ 01:42 PM

This is the fourth in a series of posts introducing open source tools Rho is developing and sharing online. Click here to learn more about Rho's open source effort, here to read about our interactive data visualization library, Webcharts, and here to learn about SAS graphing tools we've developed.

Frequent and careful monitoring of patient safety is one of the most important concerns of any clinical trial. For the medical monitors and safety monitoring committees responsible for supervising patient well-being and ensuring product safety, this obligation requires continuous access to a variety of critical study data.

For trials with large participant enrollment, severe diseases, or complex treatments, study monitors may be tasked with reviewing thousands of data points and safety markers. Unfortunately, traditional reporting methods require monitors to comb through scores of static listings and summary tables. This method is inefficient and poses the risk that clinically-relevant signals will be obscured by the sheer volume of data common in clinical trials.

To improve safety monitoring, we created a suite of interactive data monitoring tools we call the Safety Explorer. Although the safety explorer can be configured to include a variety of charts specific to each study, the standard set-up includes 6 charts (click the links to learn more):

  • Adverse Events Explorer - dynamically query adverse event (AE) data in real time to go from study population view to individual patient records
  • Adverse Events Timeline - view interactive timelines for each participant showing when AEs occurred in a trial
  • Test Results Histogram- explore interactive histograms showing distribution of labs, vital signs, and other safety measures with linked data tables
  • Test Results Outlier Explorer - track patient trajectories over time for lab measures, vital signs, and other safety endpoints in line charts
  • Test Results Over Time - explore population averages for labs, vital signs, and other safety endpoints in box or violin plots
  • Shift Plot - monitor changes in lab measures, vital signs, and other safety endpoints between study events in a dot plot

The safety explorer utilizes common CDISC data standards to quickly create consistent charts for any project. Within a given chart, users can use filters to dynamically sort, highlight, and drill down to data points of interest using controls familiar to anyone who has used a website.

Interactive Histogram with Linked Table

interactive histogram safety data

Explore the distribution of test results (click here for interactive version)

Graphical representations of data grant reviewers a systematic snapshot of the data that helps tell the story of the information. By adding interactive elements, reviewers can quickly examine the charts for patterns of interest and drill down to subject-level data instantly. This ability to quickly distinguish signal from noise, gives monitors greater insight into their data and allows them to work much more efficiently.

It is common practice for us to create safety explorers for all full service projects and studies where Rho provides medical monitoring. All of the charts described here are open source and free to use, so please let us know if you have any feedback, or would like to contribute!

Interactive Box Plot Showing Results Over Time

interactive box plot showing results over time

Track changes in population test results through a study (click here for interactive version)

View "Visualizing Multivariate Data" Video

Ryan Bailey, Senior Clinical ResearcherRyan Bailey, MA is a Senior Clinical Researcher at Rho.  He has over 10 years of experience conducting multicenter asthma research studies, including theInner City Asthma Consortium (ICAC) and the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) project. Ryan also coordinates Rho’s Center for Applied Data Visualization, which develops novel data visualizations and statistical graphics for use in clinical trials.

5 Tips for Creating a Request for Proposal (RFP) for Clinical Trial Services

Posted by Brook White on Tue, Feb 14, 2017 @ 11:13 AM

RFPs tips that allow apples to apples comparisons of clinical trial servicesIf you’re looking for a contract research organization (CRO) to provide clinical trial services, chances are you’ll need to create a request for proposal (RFP). In the complicated world of outsourcing clinical trials, using RFPs to gather comparable bids from CROs can be incredibly challenging. The good news is, with a little planning and time, you can create RFPs that will reduce inconsistencies among bidders and ultimately help you identify the CRO that is truly the right partner for the job.

Here are five tips for creating RFPs that will help you compare “apples to apples” and help the CROs better understand your needs, values, and selection criteria for your clinical trial services:

  1. Provide background information on your compound and program.  Information about other clinical studies completed or in progress, outcomes from preclinical work, regulatory strategy and even funding and marketing plans can provide context that will help a CRO understand your needs and give you a proposal that best addresses all of your concerns.
  2. Provide a protocol or protocol synopsis.  Details about the study, such as number of clinical trial sites, number of subjects, and type and frequency of procedures and assessments are important cost drivers and providing them will help ensure a more accurate proposal.  Also, an experienced CRO should also be able to make valuable recommendations based on your protocol.
  3. Provide detailed RFP information to get consistent costs. Be specific. Some examples might include:
    • Project specifications – What are the important details of your program? (Use our RFP specifications tool)
    • Project timelines – By when do you expect certain milestones to be met?
    • Responsibilities (CRO, sponsor, other vendors) – For which segments of your program do you need a CRO to provide clinical trial services?
  4. Provide additional details. The more details you can provide the better.  It’s also OK to ask questions of prospective CROsask the CRO to make recommendations. You can tell a lot about a CRO by the recommendations they make and how they make them.  However, if you ask CROs to make recommendations be prepared for potential inconsistencies in the assumptions made and pricing offered between different CROs. The following are some additional details that might be helpful to bidders:
    • Provide site locations if you have already determined which sites you want to use.  If you aren’t sure, ask for recommendations based on your target enrollment and timelines.
    • If you’ve already determined which sites you’ll be using, it is helpful to know whether they will use a central lab or local lab and also will they use a local or central IRB. This can have an impact on timelines and costs.
    • Make note of any additional vendors you need such as specialty labs, Electronic Patient Reported Outcomes (ePRO), translations, meeting planners, or imaging services.
    • Will you be using paper or EDC? The vast majority of trials are now using EDC, but there may be some small studies or specific circumstances where paper still makes sense.
    • Do you want your data output in CDISC format? Based on the FDA’s guidance, new studies must be submitted in CDISC format, so it is strongly recommended.
    • If you are planning an interim analyses or will need support for a DSMB, make sure to include this information.
    • Will you use automated subject randomization (IVRS or IWRS)?
    • What are your plans for clinical supplies and distribution (IP management)?
    • Are you interested in risk-based monitoring strategies?  If so, include this information in your RFP. Incorporating remote monitoring or targeted SDV strategies could impact the budget.What are your plans for clinical supplies and distribution (IP management)?
    • Do you want the CRO to be responsible for the TMF?  If so, ask about whether they use an eTMF and if so which one.
    • If you know you want to use specific vendors (i.e. you know you want to use Medidata RAVE for EDC), be sure to include that information.
  5. Other items to request from CROs:
    • Project team CVs including the project manager, lead CRA, lead data manager, medical monitor, and lead statistician
    • Summary of team therapeutic experience and experience running similar trials
    • Relevant company information
Download: RFP Specifications Tool