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Cellular Therapy Studies: 7 Common Challenges

Posted by Brook White on Tue, May 15, 2018 @ 09:34 AM
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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.

Kristen Much, Senior BiostatisticianKristen Mason, MS, is a Senior Biostatistician at Rho. She has over 4 years of experience providing statistical support for studies conducted under the Immune Tolerance Network (ITN) and Clinical Trials in Organ Transplantation (CTOT). She has a particular interest in data visualization, especially creating visualizations within SAS using the graph template language (GTL). 

Cellular therapy is a form of treatment where patients are injected with cellular material. cell therapyDifferent types of cells can be utilized such as stem cells (such as mesenchymal stem cells) and cells from the immune system (such as regulatory T cells (Tregs)) from either the patient or a donor. In many cases, these cells have been reprogrammed to carry out a new function that will aid in the treatment of a disease or condition. Cellular therapy has become increasingly-popular largely due to the fact that cells have the ability to carry out many complex functions that drugs cannot. When successful, cellular therapy can result in a more targeted and thus more effective treatment. More information on cellular therapy can be found here .

Rho is conducting several studies using cellular therapy to treat diseases such as systemic lupus erythematosus and pemphigus vulgaris and for various applications within organ transplantation.

Cellular therapy trials offer their own unique set of challenges. The following list presents some of these challenges encountered here at Rho.

  1. Cellular therapies require highly-specialized laboratories to manufacture the investigational product, especially if the cells are being manipulated. Centralized manufacturers are commonly utilized requiring logistical considerations if the trial has multiple study sites. These logistics may include proper packaging, temperature storage, shipping days, etc. which all must be considered when shipping the product.
  2. It is critical to plan for and establish clear communication between the manufacturing lab, the study site, and the study team when working under time constraints. One common consideration is to ensure extracted cells will not arrive at the manufacturer on a Saturday or Sunday when lab personnel may not be available to immediately process cells. 
  3. Protocols usually require a minimum number of cells be available for infusion into the subject. The protocol must detail what steps to take when not enough viable cellular product is produced. Some questions to consider include: 
    • Is it is possible to recollect cells for a second attempt? If so, does it work with the timing of the trial?
    • Are there leftover cells from the first attempt? 
  4. Potent drugs are sometimes paired with administration of the cellular product.  It is crucial to avoid administering these drugs unless a viable cellular product has been produced. Checks should be in place to ensure product is available before administering additional study drugs.
  5. Guidance exists limiting the amount of blood that can be collected over an 8-week period from a single subject. If the cellular product is manufactured from a blood donation, the amount of blood from any and all blood draws around the same time should be taken into consideration. If the blood donation occurs close to screening when blood is often drawn for various baseline labs pay close attention to the total amounts as exceeding the established limits can be easy. 
  6. The subject accrual for a study should be clearly outlined in the protocol. Is it X number of subjects that receive a minimum number of cells, X number of subjects that receive any cells, etc.
  7. Cellular product may not be administered until several months into the study. Subjects may be evaluated for eligibility several times while waiting for the infusion allowing multiple time points each subject may become ineligible. This along with the potential of insufficient cellular product can result in an unexpected length of time to administer cellular product to the target number of subjects. As such, this is an important factor when determining the duration and budget for a cellular therapy study. 
All in all, there are numerous opportunities for learning when using cellular therapies to treat disease. In many disease areas, this concept is still novel and study teams are facing new challenges with each study. Understanding these challenges early can help in the development of a robust protocol that addresses these same challenges before they ever become an issue.

Breaking Bad (Meetings)

Posted by Brook White on Tue, Sep 19, 2017 @ 10:57 AM
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Ryan2.jpgRyan 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. 

In Hamlet, Shakespeare posed the most famous existential question in English theater -- “To be, or not to be?”

If the Bard were to write a play for the 21st century office, he might ask a different, but no less poignant, question – “To meet, or not to meet?”

Few topics seem to elicit more workplace dread than the meeting. We tend to view meetings as disruptions, time sinks, resource devourers, and productivity killers. When someone says they “spent all day in meetings,” we don’t assume they got a lot accomplished; we assume their day was a bust.

Given the angst that seems to accompany meetings, we’ve been trying to rethink how we approach them at Rho. To help, we’ve been drawing inspiration from Deep Work, by Dr. Cal Newport. The premise of Deep Work is that our technology-driven culture is inadvertently inhibiting our ability to do focused, cognitively-demanding, high-impact work. Instead, our work is increasingly defined by fragmentation, interruption, and distraction, as we let our inbox and meeting schedule dictate the work we do.

Dr. Newport’s work struck a chord with us. Yet, we cannot escape the fact that our work requires the type of synchronous collaboration and context-rich communication that only meetings can provide. Here again we have an existential question: If meetings are so fundamentally important to our work, why are they so painful and disruptive?
Our honest take: We’re bad at them and we overuse them.

Most of us stink at meetings. We stink because we’ve fallen into the trap of thinking that meetings are easy. We show up and talk about the same stuff every week for an hour. What’s hard about that? In reality, effective meetings require thoughtful planning and careful execution from leaders, as well as mindful preparation and active participation from attendees.boring_meeting.jpg

Calendar software has exacerbated our problem by making it too convenient to schedule meetings. Rather than stopping to think if a meeting is needed, or if our objectives could be accomplished in a more effective way, we schedule the meeting because it’s easy. The classic example of this is the status update meeting. If the whole point of your meeting is to go around the room and give status updates to your teammates – something that could be done via email or chat with far less disruption – you have created a zombie meeting, an undead horror sucking the productivity out of your colleagues!

Many of us also have the bad habit of scheduling meetings as a form of procrastination. Instead of trying to solve a problem now, we punt it to our next meeting. While there’s nothing wrong with deferring a difficult issue until you can discuss it as a team, swamping the agenda with our postponed to-do lists is certain to “zombify” a meeting. The especially painful result of this tactic is that instead of taking a few minutes to solve the problem on our own, we multiply the resource burden. A 15-minute task dragged into an 8-person meeting effectively becomes a 2-hour task.

So, what’s to be done to salvage meetings and make them productive and engaging? One approach that we advocate among both meeting leaders and attendees is to follow the FSB mantra to meetings: Fewer. Shorter. Better. Here’s some advice we recently provided to our employees about FSB meetings:

Fewer – The challenge here is to not merely cut meetings, but to cut intelligently.  

  • Leaders: Think critically before you schedule a meeting.  Do you really need it?  Can you accomplish your objectives in a better way? For recurring meetings, take a look a day ahead of time and decide if you can cancel it. 
  • Attendees: Think critically before you attend a meeting. Do you need to be there? Read the agenda. Do you know which topics pertain to you? What will you contribute or learn? If you are unsure, contact the meeting coordinator and ask.
One alternative to cancelling a meeting is to rethink your meeting format. Could updates be sent from email and the meeting cancelled outright? Would a brief stand-up meeting suffice instead of an hour-long time drain? What about a brief teleconference from your desk? wood-table-meeting.jpg


Shorter – Meetings are notorious for taking up as much time as you allot for them. When you have back-to-back meetings, this leads to meeting room overlap, frustration, and the domino effect of late-starting meetings. Instead, try the 25/50 rule: reduce 30-minute meetings to 25 minutes and hour-long sessions to 50 minutes. This provides buffer to conclude your meeting and head to your next engagement on time.

Better – The single most important factor for better meetings is being prepared. Not knowing why you are at a meeting, what will be discussed, and what you hope to accomplish is certain to create a poor meeting.

  • Leaders: Serve your attendees well by following the basics of good meetings: 
    • Have a goal
    • Think critically about who should attend
    • Provide context ahead of time
    • Stay on time and on task
    • Endeavor to engage everyone in the room

If you are struggling with these steps, try setting aside time to prepare for your meetings.  You may also find that you are leading too many meetings.  In which case, you should share the load (this is a great way to help train up more junior team members!)

  • Attendees: Don’t settle for bad meetings.  Speak up and provide helpful, candid, and constructive feedback.  But also, when you’re in a meeting, be a helpful attendee:
    • Request that items be added to the agenda ahead of time
    • Come prepared to address the sections of the agenda you’re responsible for
    • Avoid the temptation to commandeer or disrupt the meeting

Meetings don’t have to be a source of frustration or disruption.  To the contrary, meetings can be some of the most productive times of our day – where we solve problems, brainstorm, and find creative inspiration – provided we execute them properly.  

When is the last time you did a self-evaluation of your meetings?  If it’s been a while (or never), consider taking 15 minutes this week to think critically and creatively about your current meetings.  How can they be pared back, truncated, and refined to make them more effective and productive?  When done right, following the FSB mantra can do a lot to return some much-needed productive time to your schedule.

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Beating the Odds: 5 Strategies to Improve Clinical Trial Enrollment

Posted by Brook White on Tue, Jul 18, 2017 @ 10:03 AM
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Brandy Lind, Senior Director OperationsBrandy Lind, Senior Director of Operations, has been in project management at Rho since 2004.  During this time, she has led several large programs and individual projects in multiple therapeutic areas.  She has worked on observational trials, interventional trials, and Phase I-III clinical trials throughout her career.

According to a 2013 report by the Tufts Center for Drug Development, timelines are typically extended to nearly double their original duration in order to meet enrollment goals which is a significant contributor to increased costs.  Hitting the clinical trial enrollment goal is not only important to meeting overall study timelines and budgets, it is critical to the success of the clinical study.  If you don't have enough participants, you won't have enough data to support your objectives.  That's why it's important to plan for enrollment just as you would plan for collecting and analyzing the data. In this post, we’ll share 5 keys to successful enrollment.

1. Identify sites with the most potential

choose the sites with the most potential, choose the biggest marbleIt all starts by choosing the right sites.  Research sites with experience in your therapeutic area.  Are there existing site networks that can be leveraged?  Check clinicaltrials.gov  to see which sites are currently participating in similar studies or have in the past. One of the best ways to find qualified, high performing sites is to reuse sites that have demonstrated both an ability to enroll and produce high quality data.  Past performance is one of the best indicators of how sites will perform on future studies.

Put the time in up front to complete a full feasibility.  It can be tempting to jump right into site start-up, but time and money spent on feasibility upfront can save you time and money downstream by preventing protocol amendments and enrollment struggles.  Ask sites about how they identify subjects, how many patients are already in their database, and how many patients come to their facility each month.  Find out what they do when they have exhausted their own database.  Competing studies can impact their ability to enroll on your study, so find out if they are currently conducting other studies in the same patient population.  If they are, press for information about whether they have access to enough patients for both studies or if inclusion/exclusion criteria are different enough to allow them to support both.

Get feedback from sites on the eligibility criteria and feasibility of operationalizing the protocol.  They may have suggestions for changes that can increase the enrollment rate without impacting the scientific integrity of the protocol.  The sites also know the patients well and can help you assess patient interest.  Consider whether the indication is serious enough that patients will want to participate and also consider existing therapies that are available to patients that may impact enrollment.

Study logistics can also impact patients’ willingness to participate, so consider the burden the schedule of events will place on participants.  How long will visits be?  Will they have to stay overnight?  Does transportation to and from the site present an obstacle for patients?  If you have an elderly or pediatric population, consider the impact on caretakers and how they will need to be involved in the process.  Sites can help you identify opportunities to ease these burdens for study participants and their caretakers.

Finally, prioritize sites based on start-up timeframe, recruitment potential, and previous research experience.  Make sure you also identify some back-up sites that can replace underperforming sites or be added later to boost enrollment.  You can achieve some efficiency by getting these sites through start-up along with the main sites you have identified.

2. Set expectations with sites

Make sure you set clear expectations with sites from the beginning rather than waiting until you start to see issues.  CRAs should work closely with each site to develop an individualized enrollment plan.  Where will they get patients?  What recruitment materials will work best for their site?  Are there other healthcare providers they can network with to gain additional participants?  A one-size-fits-all approach to recruitment rarely works.

Once sites are activated, have routine calls, individually and as a group, to discuss clinical trial enrollment strategies and plans.  Have sites share what’s working and what’s not, share ideas, and build relationships.  Find out from sites why patients don’t want to enroll.  If you do have to adjust the protocol, the earlier the better. During group calls, have your high performing sites share lessons learned, tips, and successes. 

Develop a plan for how you will address sites who are not meeting enrollment expectations.  Give them all the support you can, but also be prepared to follow through with your mitigation plan if they are not able to turn things around.

3. Start with accurate projections

start with accurate projections of enrollment ratesIt is tempting to create timelines based on best case scenarios.  Excitement about getting a new product to market, helping patients, and meeting investor expectations can all be strong motivators to be overly optimistic about enrollment projections, but this will just create more delays and increase costs downstream.  Be realistic about how many patients each site can enroll each month based on feasibility -- you (and your investors) don't want surprises!

Consider study-specific issues that may affect enrollment like seasonal effects.  Create graphics to show expected enrollment over time versus actual enrollment to date. Having this information at your fingertips can help you make informed decisions about whether to add a back-up site, change recruitment methods, and project when actual enrollment is likely to end.  Use this information to continually reassess your upfront assumptions, so you can be proactive if enrollment isn’t moving forward as expected.

4. Build relationships with sites

Maintaining strong relationships with sites is critical.  They provide key insights into the therapeutic landscape.  They are close to patients and can help you understand patient concerns and perspectives, which can help improve recruitment and retention.  

Use the investigator meeting as an opportunity to build and strengthen these relationships.  Explain the importance of the study and the potential benefits for the patient population.  Engage sites and make them a partner in your research. Creating a situation where sites want to work with you again will be of great benefit to future studies!

5. Collaborate with your CRO

handshake.jpgLook for a CRO that acts as an extension of your team and sees your study as a collaborative endeavor.  During enrollment, it's important to have constant communication between the Sponsor and CRO regarding the status of site activations and enrollment numbers, risks to the clinical trial if we are not on track to hit the goals, and mitigation strategies to get enrollment back on track.

7 Tips to Use Social and Digital Media to Recruit and Engage with Clinical  Trial Patients

Why Depression Studies So Often Fail:  Don’t Blame “Placebo Response”

Posted by Brook White on Thu, Jun 29, 2017 @ 02:34 PM
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Jack Modell, Vice President and Senior Medical OfficerJack Modell, Vice President and Senior Medical Officer, is a board-certified psychiatrist with over 35 years of experience in clinical research, including 20 years conducting trials, teaching, and providing patient care in academic medicine, and 15 additional years of experience in clinical drug development (proof of concept through market support), medical affairs, successful NDA filings, medical governance, drug safety, compliance, and management within the pharmaceutical and CRO industries. Jack has authored over 50 peer-reviewed publications across numerous medical specialties and has lead several successful development programs in the neurosciences. Jack is a key opinion leader in the neurosciences and is nationally known for leading the first successful development of preventative pharmacotherapy for the depressive episodes of seasonal affective disorder.

Prior to joining the pharmaceutical and contract research organization industries, I was in clinical practice for twenty years as a psychiatrist and medical researcher.  And something I noticed very early on among my patients with major mental illnesses, particularly those with severe depression and psychotic disorders, was that they did not generally get better – at least not for more than a day or two – by my simply being nice to them, treating them with ineffective medications (e.g., vitamins when no vitamin deficiency existed), seeing them weekly for office visits, or by providing other so-called supportive interventions that did not directly address the underlying illness.  To be clear, this is not to say that kindness and supportive therapy are not critical to the patient-physician relationship (“The secret of the care of the patient is in caring for the patient” [Frances Weld Peabody, 1927]), but rather that kindness and support alone rarely make a biologically based illness substantially improve or disappear. 

With this background, I vividly recall my surprise upon being asked shortly after I joined the pharmaceutical industry:  “Can you help us figure out how to decrease the nearly 50% placebo-response rate we see in antidepressant trials for major depressive disorder?”  “Fifty percent?” I replied, incredulously.  “There’s no way that 50% of patients in a true major depressive episode get better on placebos or just by seeing the doctor every couple of weeks!”  “Seriously?” was the reply, and they showed me voluminous data supporting their figure.

I spent the next few years trying to figure out this apparent paradox.  Not surprisingly, the answer turned out to be multifactorial.  After careful review of internal and external data, as well as published explanations for high “placebo response rates” in clinical depression trials (much of which also applies to clinical trials in general), the following three factors emerged as being of particular importance because they are easily mitigated by proper trial design, thorough research staff training, and meticulous oversight of study conduct.

(1)  Subjects being admitted into clinical trials often had depressive symptoms, but did not truly meet criteria for major depressive disorder.  Examples include subjects with personality disorders whose symptoms wax and wane considerably with external factors (e.g., family or job stress), subjects with depressive symptoms in response to a particular stressor (not of sufficient severity or duration to meet formal criteria for a major depressive episode and likely to abate with the passage of time), and subjects who – for various reasons – may feign or exaggerate symptoms for the purpose of seeking attention or gaining access to a clinical trial.  Unlike the patients I encountered in my clinical practice, subjects with these presentations often do improve with supportive interventions and placebo. 

Recruitment of truly depressed subjects is made even more difficult by the widespread availability of reasonably effective medication options. Patients in the throes of a major depressive disorder, who sometimes have difficulty even making it through the day, are rarely keen to commit to the additional efforts, uncertainties, and treatment delays involved with a clinical trial when an inexpensive prescription for an effective generic antidepressant can now be filled in a matter of minutes. Indeed, as more and more generally safe and effective medications have become approved and readily available for a variety of illnesses, the motivation for patients to join clinical trials in the hope of finding an effective treatment has correspondingly decreased.

(2) The second factor is somewhat difficult to discuss because it sometimes provokes an understandable defensive response in clinical investigators.  Consciously or unconsciously, many investigators and clinical raters inflate or deflate clinical ratings to enable the subject to gain entry into, or remain enrolled in, a clinical trial.  Most commonly, this is done by subtly – and sometimes not so subtly – coaching subjects on their answers, or when subject responses or findings seem to fall in between scale severity ratings, by rounding up or down to a rating that is more likely to qualify the subject for the trial. 

The effect of this practice is diagrammed in the following figures, specific examples of which can be seen in these references.1-3 In Figure 1, the white bell-shaped distribution is the expected distribution in severity rating scores of an unselected clinical population presenting for clinical trial participation, let’s say with a mean score at shown at X̄n. Not uncommonly, what we see in clinical trials in which a certain scale severity score is required for study entry (depicted by the vertical light blue line, with a score to the right of it required for entry) is not the expected right half of this bell-shaped distribution, but rather a distribution like that shown by the orange curve, which is essentially the right-half of the bell-shaped distribution with a large proportion of subjects whose ratings fell short of required severity for study entry (to the left of the blue line) “pushed” to the right, over the blue line, so that the subjects now qualify for study inclusion, with the mean of those thus selected shown at X̄s.

Figure 1

depression-fig-1.jpg

At the first follow-up visit, when raters (and subjects) now have little incentive to influence rating scores to meet a pre-specified criterion, the scores of the entire included population are free to relax towards their true values and assume the pre-selection and more normally distributed pattern.  Moreover, subjects and investigators, expecting that the onset of treatment should coincide with at least some clinical improvement, may bias rating scores during this period to reflect this expectation even though the signs and symptoms of the illness may have yet to show true change.  During this same time, any actual clinical improvement will also result in the rating score mean shifting leftward (white arrow, figure 2), but because the measured change – from the initial X̄s of the selected population to the new mean (X̄n1; orange arrow, figure 2) – is generally much greater than a true treatment effect during this period, any real changes are obscured and the ability to detect a true drug-placebo difference may be lost.  While this early “improvement” in rating scores for subjects in clinical trials may appear to be a “placebo effect” and is often confused with it, this apparent improvement is instead the result of artificially inflated scale scores regressing back to their original true distribution, in combination with whatever actual treatment and placebo effects may have occurred during this time.  Unfortunately, the introduction of non-qualified subjects to the study and rater bias will continue to hamper detection of actual drug-placebo differences throughout the course of the study.

Figure 2

depression-fig-2.jpg

(3) Finally, investigators and site staff often do not fully understand the true objective of the clinical trial:  it should never, for example, be “to show treatment efficacy” or to show that a product is “safe and well tolerated,” but rather, to test the null hypothesis of no treatment difference or to estimate likely treatment effect, as well as to faithfully and objectively record all adverse effects that may emerge during treatment.  Likewise, investigators and site staff often fail to understand the importance of complete objectivity and consistency in performing clinical ratings, the intention behind and importance of every inclusion and exclusion criterion (necessary for their proper interpretation and application), and the destructive effect on the outcome and scientific integrity of the trial that even well-intended efforts to include subjects who are not fully qualified can have.  

Each of these three factors can skew both drug and placebo trial populations and results, making it appear that subjects “improved” well beyond what would have resulted had there been strict adherence to protocol requirements and objective assessment of study entry and outcome measures.

What, then, can be done to prevent these problems from sabotaging the results of a clinical trial?  Foremost are thorough and meticulous investigator and rater education and training.  All too often, perfunctory explanations of the protocol and clinical assessment tools are provided at investigator meetings, and “rater training” takes the form of brief demonstrations of how the rating scales are used and scored, without actually testing raters to be certain that they fully understand how the scales are to be used and interpreted, including understanding scoring conventions, criteria, and necessary decision-making.4  Even seemingly sound training has marked limitations both immediately and as training effects deteriorate during conduct of the trial.4-7 

Training of the research staff must include not only a review of the protocol design and study requirements, but detailed explanations about why the trial is designed exactly as it is, the importance of strict adherence to study inclusion and exclusion criteria, and the necessity for complete honesty, objectivity, and consistency in conducting the clinical trial and in performing clinical assessments.  Detailed training on the disease under study is also important to ensure that all site staff have a complete understanding of the intended clinical population and disease being studied so that they can assess subjects accordingly.  And, as noted above, rater training must include not only education on the background, purpose, characteristics, and instructions for each scale or outcome measure used, but trainers, as well as investigators and raters, should be tested for adequate understanding and proficiency in use of each of these measures. 

Meticulous monitoring during the course of the study is also essential to ensure continued understanding of, and compliance with, protocol requirements, as well as accurate and complete documentation of study procedures and outcomes.  Study monitors and others involved with trial oversight should review data during the course of the trial for unexpected trends in both safety and efficacy data, and not simply for identification of missing data or isolated datum outliers.  Unexpected trends in safety data include adverse event reporting rates at particular sites that are much higher or lower than median reporting rates, and vital signs that are relatively invariant or favor certain values over time.  Unexpected trends in efficacy data include changes in closely related outcome measures that are incongruent – for example, objective and subjective ratings of a similar outcome differing considerably in magnitude or direction, that are much larger or smaller at particular sites than those observed at most sites, that occur in relatively fixed increments, and that show unusually similar patterns or values across subjects. 

Finally, and perhaps most importantly, is that no matter how well-informed or well-intentioned investigators and raters might be, humans simply cannot match computers in objectivity and consistency, including of the kind needed to make assessments based on subject responses to questions in clinical trials.  Unless being programmed to do so, a computer cannot, for example, coach a subject on how to respond, nor would it inflate or deflate ratings based on feelings, expectations, response interpretations, or desired outcomes.  A computer faithfully asks the same questions every time, following the same algorithm, and records responses exactly as provided by the subject.  Indeed, several studies have shown that computerized assessments of entry criteria and outcome measures in clinical trials – in particular interactive voice response systems (IVRS) and interactive web response systems (IWRS) – provide data of quality and signal-detection ability that meet and often exceed that obtained by human raters.1,3,7,8,9  For these reasons, strong consideration should also be given to using IVR and/or IWR systems for assessing study entry criteria and endpoints that allow such use.  

The author acknowledges John H. Greist, MD, for his outstanding research and input regarding these important findings and considerations.

References

  1. Greist JH, Mundt JC, Kobak K.  Factors contributing to failed trials of new agents:  can technology prevent some problems.  J Clin Psychiatry 2002;63[suppl 2]:8-13.
  2. Feltner DE, Kobak KA, Crockatt J, Haber H, Kavoussi R, Pande A, Greist JH.  Interactive Voice Response (IVR) for Patient Screening of Anxiety in a Clinical Drug Trial.  NIMH New Clinical Drug Evaluation Unit, 41st Annual Meeting, 2001, Phoenix, AZ.
  3. Mundt JC, Greist JH, Jefferson JW, Katzelnick DJ, DeBrota DJ, Chappell PB, Modell JG.  Is it easier to find what you are looking for if you think you know what it looks like?  J Clinical Psychopharmacol 2007;27:121-125.
  4. Kobak KA, Brown B, Sharp I, Levy-Mack H, Wells K, Okum F, Williams JBW.  Sources of unreliability in depression ratings.  J Clin Psychopharmacol 2009;29:82-85.
  5. Kobak KA, Lipsitz J, Billiams JBW, et. al.  Are the effects of rater training sustainable?  Results from a multicenter clinical trial.  J Clin Psychopharmacol 2007;27:534-535.
  6. Kobak KA, Kane JM, Thase ME, Nierenberg AA.  Why do clinical trials fail.  The problem of measurement error in clinical trials:  time to test new paradigms?  J Clin Psychopharmacol 2007;27:1-5.
  7. Greist J, Mundt J, Jefferson J, Katzelnick D.  Comments on “Why Do Clinical Trials Fail?”  The problem of measurement error in clinical trials:  time to test new paradigms?  J Clin Psychopharmacol 2007;27:535-536.
  8. Moore HK, Mundt JC, Modell JG, Rodrigues HE, DeBrota DJ, Jefferson JJ, Greist JH.  An Examination of 26,168 Hamilton Depression Rating Scale Scores Administered via Interactive Voice Response (IVR) Across 17 Randomized Clinical Trials.  J Clin Psychopharmacol 2006;26:321-324.
  9. http://www.healthtechsys.com/publications/ivrpubs2.html 

Webinar: Selecting Inclusion/Exclusion Criteria for Your Next Trial

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
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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 1—Overview

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

patien-centricity-elephant.png

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
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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.

ICH E6 R2

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
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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.

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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
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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.

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How Stable Is Your CRO?  And Does It Matter?

Posted by Brook White on Wed, Feb 01, 2017 @ 11:15 AM
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CRO stabilityClinical trials are a costly business.  In 2013 alone, the biopharmaceutical industry spent nearly $10 billion on clinical trials.  Operational failures in clinical trials can increase those costs and create delays in time to market. So when you pick a CRO, you want to ensure that at best they are mitigating operational risks, and at worse aren’t introducing new ones. Stability can play a significant role in this.

Corporate stability

When looking to outsource to a CRO, there are several aspects of corporate stability that should be assessed:

  • How long has the CRO been in business? The newer the company, the more likely that they don’t have the overall experience you may need. Additionally, they have a shorter history with their clients, so it will be difficult to assess past customer satisfaction.
  • Are they financially stable? A company that isn’t profitable, has a lot of outside debt, or is under strain from shareholders or investors may be making short-term business decisions that aren’t in the best interests of your study or program. Worse yet, they could go out of business in the middle of your clinical study or run into cash flow issues that impact the success of your clinical trial.
  • Have they recently been involved in M&A activity, have they gone public, or are there plans to do so? This type of activity typically comes with significant organizational impacts that can bleed over into day-to-day activities. From changing SOPs mid-study to project team turnover, it rarely has a positive impact in the short-term for existing clients.

Consider incorporating questions about these topics into a request for information (RFI) or as part of the request for proposal (RFP) process.  These are valid questions that CROs are used to addressing, so be wary of companies that are reluctant to do so.

Client Stability

client stabilityA good measure of how well you will be treated once the contract is signed is the satisfaction of existing and former clients.  You should look for a CRO that has long-standing relationships with many of their clients.  You’ll often see CROs that have slides listing the logos of their clients or with testimonial quotes from clients.  That’s all well and good, but you need to check for yourself.  Ask for references whose work is of similar scope and for similar services as those you are planning to outsource.  Contact references directly rather than relying on the CRO to act as an intermediary.

People Stability

happy project teamEmployee turnover rates across the CRO industry are incredibly high. In 2015, CRO turnover was 25% despite the fact that team stability is a key factor in meeting sponsor expectations and in doing high quality clinical research. Make sure you ask both about turnover and about the tenure of your assigned team. A team with multiple members that have recently joined the company should be a red flag. In addition to company turnover, find out what you can about project team stability. Keeping a team together over the course of a study means less re-training, fewer mistakes, and less re-work. There is a learning curve with each new sponsor and product. If you are considering outsourcing multiple trials particularly within the same program, ask if the same team members can be assigned to future studies.

Learn more about selecting a CRO by checking out the outsourcing tips on our blog.

Download: RFP Specifications Tool