Marylyn Donahue

Editor’s Note: This article is part of a series examining popular peer-reviewed articles from years past called “Peer-Reviews Revisited: Why You Should Read Today.” You can read the other articles in this series 

The image acquisition and analysis components of R&D and clinical trials can be quite complex, so complex that it can leave even the savviest sponsors and CROs facing the I-don’t-even-know-where–to-begin dilemma.  

And yet, a critical part of the trial protocol is the "power" variable, or the number of patients required to reach 90% to 95% confidence such that statistical significance can be reliably concluded at the end of a trial. Inevitably, in order to reach such significance in a highly variable human population the recommended number of patients in these studies can be quite large. Unfortunately, with large patients cohorts, the effort, time, and cost required to analyze and score all of the medical image data acquired during the trial can increase exponentially and pose a significant barrier in getting a new medical device or therapeutic to market. Harnessing the power of imaging analytics and incorporating them into a clinical study is not a simple task, but the benefits gained can make it a worthwhile investment. 

The good news is rapid advances in image acquisition technology and continued developments in image analysis software are changing the depth and breadth of clinical research. Imaging permeates clinical and basic research across many scientific disciplines including oncology, orthopedics, ophthalmology, cardiology, and neurology, and across entities focusing on pharmaceuticals, medical device development, cell and molecular biology, tissue engineering and beyond.

The challenge for the investigator then is to stay current on the state-of-the-art in imaging and image analysis, let alone the imaging-related requirements for preclinical and clinical trials. He or she must also know how to figure in availability and, of course, cost along with other factors particular to the trial.

In this peer-reviewed article “Art & Science of Imaging Analytics” that appeared in Applied Clinical Trials in March 2013, authors Amit Vasanji and Brett A. Hoover tell you everything you need to know about the state of Imaging and guide you through the acquisition process.

Once integrated, these new approaches to imaging and analysis provide a number of other benefits as well:

Increased precision, throughput and objectivity of outcome metrics with automation of traditionally manual image scoring processes

Reduced likelihood of unexpected delays due to personnel turnover and expertise unavailability

Reduced cost and guesswork associated with clinical trials with more comprehensive and quantitative data and potentially smaller patient cohorts

Improved ability to communicate and leverage study results through quantitative data renderings and visualizations (2D or 3D)—collateral for market adoption

Articles

The image acquisition and analysis components of R&D and clinical trials can be quite complex...

Everything You Need to Know About Imaging Analytics For Clinical Trials

Until relatively recently, taking your company's clinical research into the realm of electronic data capture (EDC) meant going with a full service vendor with a price tag generally starting at $175,000 to $200,000 for a 250 patient, 50 site trial over 24 to 36 months, and as high as your project was complex. If you wanted to conduct smaller scale research, these were often just not economically feasible—the same pricing as just mentioned might be provided for a 50 patient, five-site trial.

Why not "do it yourself" (DIY), then? Certainly it is an available option to decrease costs from some of the larger EDC companies, but often only less expensive if you are doing large volumes of research and can afford to have skilled "build" specialists trained and on staff. 

Again, the net result is that smaller companies either remain in a paper world with all its attendant woes, or are compelled by cost-containment needs to select markedly sub-par EDC systems almost as problematic as the old paper model.

Over the past three to four years, however, viable DIY EDC options have begun to emerge onto the marketplace that make what has become a commonplace technology in larger organizations more accessible economically to smaller enterprise. 

As every weekend warrior tackling an at-home project knows, you may be doing it yourself, but you still need expert guidance. This is a thousand times truer when it comes to finding, assessing, and selecting DIY EDC. And it is by no means as simple as it might at first appear. 

Timothy Pratt, PhD, in this peer-reviewed article that first appeared in 

has both lived through the process for himself and also recently tested it for a small medical device company. He takes you through each step along the way, which turns out to be not unlike a beauty contest— a process of elimination.

Except in this contest there's a rigorous first step—finding the contestants. It is a relatively new field. As his most useful resource, he cites the 

Applied Clinical Trials' Annual Buyer's Guide. 

With each step, Pratt supplies both what you need to look for and also what you need to look out for—the pitfalls—and what questions to ask to avoid them. This standardization assessment process that includes systematic scoring of vendors and their offerings, Pratt sees this as critical to the selection process whether it be in the areas of pricing or performance. 

"Finding and assessing an electronic data capture methodology is a task that must be approached methodically in a structured manner," says Pratt.  "EDC systems vary so much in capabilities that the only valid way to make good judgments on suitability is via standardization of the method of assessment. This is especially true for the smaller life sciences company that may not have the in-house expertise to rely upon, and seeking CRO or consultant help may be invaluable. Enabling cross-vendor pricing comparisons through use of models can reveal critically important information on product scalability and economic feasibility for different project types. Finally, careful consideration of your company's specific needs may lead to weighting of particular components or dimensions of DIY systems which can help differentiate vendors when a clear 'winner' is not present."

What's been a commonplace technology for larger organizations is now becoming more accessible economically to smaller enterprises. But how to choose?

87 Questions To Consider: A Must-Read Guide To Assessing Key Areas of a DIY EDC Option for Your Company

Patients there respect and trust their doctors and do what he or she tells them to do...like participate in a clinical trial

10 Reasons to Make the Baltic States A Location for Your Next Clinical Trial

All-told the Mayo Clinic’s pilot study recruitment using social media and online networks not only helped researchers assemble large and demographically diverse patient groups more quickly, but also they did it less expensively than they could through other means.

“This study is a prime example of patient-initiated research that could be used by other health care professionals and institutions,” conclude the authors of the Mayo report.
 But can the Mayo Clinic’s pilot study really be used “by other health care professionals and institutions?” 

Was the success of their social media recruitment so easily translatable? Or was their pilot study the result of a perfect storm—A series of factors coming together to make it just the right opportunity for social media recruitment, and anything but commonplace. 

Digital Strategy & Patient Recruitment for Clinical Trials,

 Rahlyn Gossen examines six key patient recruitment factors that resulted in the Mayo’s pilot study’s success and a perfect social media fit. (Not to be overlooked in all of this is the Mayo Clinic’s sophisticated, savvy, and deep appreciation of social media). 

Gossen, a former clinical research coordinator who now has her own firm, 

Concentrated and organized patient population 

Patient-initiated research and ownership for success 

Favorable demographics for patient recruitment via social media 

Widespread Positive Brand Awareness (Mayo Clinic) 

“In some cases, clinical research professionals can mimic the factors contributing to Mayo’s success,” says Gossen. “But in most cases, the possibility for successful social media recruitment will largely be the result of static factors like therapeutic indication, patient population, study design, and geography. 

“Before undertaking a social media campaign for patient recruitment, it’s imperative that clinical research professionals identify pertinent variables and determine whether those variables are well-aligned with a social media recruitment campaign,” says Gossen.

It is also imperative that whomever is behind the effort is equipped with the social media skills enjoyed by the Mayo Clinic (You only have to go to their Website for a glimpse of their media expertise and sense of design). They must also be motivated by more than just a desire to sell a social media service.

“The reality is that, in many cases, patient recruitment via social media will be an uphill battle,” says Gossen. “But all is not lost. You can still recruit patients who frequent social media sites with advertising on those sites, thereby eliminating the 

challenges of patient recruitment on social media websites

 that it is important to distinguish between social media and advertising on social media platforms. “This is an area where I find there to be some confusion, and that confusion tends to muddle the discussion about social media in patient recruitment,” she said. “Social media is by nature a dialogue and requires a very different strategy and skill set than online advertising, which is more of a one-way broadcasting medium. An example of this distinction in practice is the difference between, say, putting up a Facebook page and conversing with those who are commenting versus putting up ads on Facebook. This distinction, I've noticed, is unclear regarding terminology.” 

Social media is just that social, and it requires long term engagement between participants that runs counter to say a study specific goal and just putting out the word that’s there’s a trial going on.

Whereas a tactical advertisement on Facebook can be targeted among the sites hundreds of millions of users. Its offerings for advertisers also can be highly targeted to specific geographic areas. And with such a large population, Facebook can reach a high percentage of potential patients across all levels of income and education. Traditional media can’t even touch those results.


 Peer influence to generate interest in participating in a trial is another method to generate trial recruitment. PatientsLikeMe hosts all kinds of disease communities where patients can track their medications, symptoms, and health outcomes and can learn from other patients whose profiles resemble their own. It allows the industry to look at aggregated data from its communities. And now it allows them to partner with pharma companies to announce clinical recruitment trials through its online communities. Other patient sites like 

 (utilized by the Mayo Clinic pilot study) and armyofwomen.org do the same.

Nevertheless, the uphill battle in social media recruitment Gossen referred to earlier was confirmed last spring by a survey conducted by Blue Chip Patient Recruitment and shouted out by Ed Silverman at 

Silveman adds a caveat: “The company is a division of Blue Chip Marketing Worldwide, a marketing agency that is, of course, attempting to promote its expertise by conducting the survey and disseminating the results as a worthwhile snapshot.”

Nonetheless the study found:  Of 179 adults, who were queried through postings in online health communities, 84 percent have never participated in a trial.  Twenty-two percent would enroll if a drug offered a cure and 21 percent if they could help find a cure. For the complete report: 

http://www.bcpatientrecruitment.com/main.html

Online or offline, safety also presented an issue to the survey participants: 

41 percent reported that trial safety is a primary concern

36 percent cited the credibility of the trial information found online 

88 percent would prefer receiving clinical trial info online from a doctor. 

And when asked where they would first go to learn more about a trial: 

70 percent were comfortable receiving clinical trial messages from a healthcare association rep - the example offered was the American Diabetes Association 

53 percent were comfortable hearing from an online support group 

32 percent cited a web site message board.

For those invested heavily in the favorite social media sites:

Fewer than 20 percent were most comfortable receiving clinical trial messages by way of a Facebook wall or a Twitter profile. Meanwhile, 

Only 30 percent were aware of key clinical trial websites, with 

Only 18 percent were specifically alert to ClinicalTrials.gov.

The Blue Chip’s finding are consistent with other studies on social media and online health information seeking. Gossen points out: “For example, Pew Internet’s 2011 report, 

, found that only 15% of Internet users got health information via 

Gossen also adds that this statistic would be far lower for clinical trials information seeking, which comprises a small proportion of overall health information seeking. 

In the end, using social media for patient recruitment is perhaps not so much an uphill battle as an exercise in strategy, discernment, and selection. It can work, it can even be an ideal method (as seen in the Mayo Clinic pilot study) but the particular conditions of the study must fit the social media opportunity, and not the other way around. 

Patient Recruitment via Social Media: An Uphill Battle

Social media and online networking proved to be a valuable tool for recruiting participants to a pilot study on a rare heart disease last summer at the Mayo Clinic. 

Through patient-run websites dedicated to heart conditions and women's heart health, a team of Mayo Clinic cardiologists led by Sharonne Hayes, MD, reached out to survivors of spontaneous coronary artery dissection, also known as SCAD, a poorly understood heart condition that affects just a few thousand Americans every year. 

A SCAD survivor inspired the pilot study. The woman approached Dr. Hayes asking how she could spur more research into the unusual condition. Dr. Hayes' research team then asked the survivor to help recruit participants through an online support community on the website for WomenHeart: The National Coalition for Women with Heart Disease, 

. The SCAD survivor and Dr. Hayes already were affiliated with the site.

Much discussion among researchers has taken place about how study recruitment through social media and online networks could help assemble large and demographically diverse patient groups more quickly and inexpensively than they could using traditional outreach methods, but just how and how well it would work has raised many questions. 

The Mayo Clinic patient-initiative research has supplied lots of answers in the September issue of the 

 (and quoted at length in this article) generously details the pilot study’s processes, successes, and limitations.

"Patients with rare diseases tend to find one another and connect because they are searching for information and support," says co-author Marysia Tweet, M.D. "Studies of rare diseases often are underfunded, and people with these conditions are quite motivated."

SCAD is a traumatic cardiac event that often induces heart attack, but physicians have no clinical studies on which to base treatment plans, says Dr. Hayes, lead author of the study and founder of Mayo's Women's Heart Clinic.
  "This is a completely different research model than the Mayo Clinic is used to," Dr. Hayes says. "Investigators here typically rely on the stores of patient information from the clinic. This was truly patient-initiated research."

The study landed 18 participants in less than a week, six more than could participate in this pilot of 12 patients. The remaining volunteers are eligible to participate in a new, larger study based on the initial study's success.

The new research sought patients through conventional and social media outlets and aims to build a virtual registry and DNA biobank of up to 400 SCAD survivors and their relatives. The database will help physicians conduct more detailed analyses of treatment strategies and factors that affect prognosis and better understand the possible genetic basis of some SCAD cases.

Through its Office of Rare Diseases Research, the National Institutes of Health tracks 6,000 to 7,800 rare diseases such as SCAD that affect fewer than 200,000 Americans. NIH experts can only estimate the number of rare diseases because there's not enough data to know how many patients have them, let alone how to study or treat them.

"Patient leadership in this is huge," says study co-author Lee Aase, director of Mayo Clinic's Center for Social Media. "Designing research protocols to study rare diseases and then recruiting enough patients to participate is extremely difficult for busy physicians, but patients with rare diseases are highly motivated to see research happen."

The report goes on to detail the pilot study setup: “After being approached by several members of an international disease-specific support group on a social networking site, we used it to identify patients who had been diagnosed as having at least one episode of spontaneous coronary artery dissection and recruited them to participate in a clinical investigation of their condition. Medical records were collected and reviewed, the original diagnosis was independently confirmed by review of imaging studies, and health status (both interval and current) was assessed via specially designed questionnaires and validated assessment tools.

“Recruitment of all 12 participants was complete within one week of institutional review board approval (March 18, 2010). Data collection was completed November 18, 2010. All participants completed the study questionnaires and provided the required medical records and coronary angiograms and ancillary imaging data. Identifying and recruiting study participants with rare conditions such as SCAD can be a formidable challenge because no single medical center has adequate experience and/or patient volume. A formal multicenter registry will ultimately be necessary to recruit patients early in the acute phase of their condition, and subsequently randomized clinical trials may become feasible. Until it is created, however, this unique model involving self-organized patients with SCAD provides an excellent option for a virtual multicenter registry. The rapid enrollment of participants in this pilot study through a social networking platform suggests a way to harness patient enthusiasm and organize studies that have been heretofore impractical.

“Data that could be collected in this manner include clinically relevant information about demographics, natural history in survivors, and treatment patterns. We found the personal narrative prepared by participants about their disease and health care experiences to be extremely helpful in filling in gaps in medical history, clarifying time lines and generally complementing the medical records in a manner similar to obtaining a face-to-face clinical history. As in other registries, findings can generate hypotheses and future inquiry. Our report serves as a proof of concept, and extending enrollment to the almost 100 women with SCAD currently on Inspire.com will produce the largest SCAD registry to date and allow development of an imaging and DNA database to complement the retrospective assessment. Moreover, in the future this process could be extended via online surveys and development of electronic centralized data repositories with direct health record data transfer, assuming data security and Health Insurance Portability and Accountability Act compliance could be ensured.

“Obtaining complete medical records is crucial for this type of review. Our participants were highly motivated to provide all requested records. We were impressed with the successful collection of original diagnostic coronary artery imaging for review in all of our pilot participants despite their geographic diversity, the challenges of our medical record retrieval system, and the lack of participants' preexisting clinical relationship with the investigators. Several participants asked their personal physicians to contact us to confirm our data needs, and three potential study participants' physicians contacted an investigator (S.N.H.) at the patients' request to ensure that our study was “legitimate.” 
  Given the possibility of Internet scams and the fact that the patients had not yet received communication directly from the Mayo Clinic study team, the physicians’ reactions reflected appropriate caution. 

“In future studies, posting key information available on Mayo Clinic's Web site for institutional clinical trials before the notice goes “viral” on the patients' social networking site will be important,” says the team.

In-person support groups for conditions as rare as SCAD have proven to be impractical if not impossible.

Only a few dozen SCAD survivors are likely to reside in even a large metropolitan area. “An online site with no geographic limitations is more likely to reach critical mass,” cited the report.
              
  Social networking tools have had important health and humanitarian effects ranging from crowd-sourced epidemiology studies to earthquake relief. 

 have enabled populations affected by a mass incident to easily pool and organize their knowledge. New York University professor Clay Shirky calls platforms like these mechanisms for harnessing society's “cognitive surplus.” 

The Mayo Clinic pilot study points out that their approach differed from those projects in that it applied social tools not in “headline-grabbing localized events such as pandemics and earthquakes, but rather to an unusual condition unnoticed by the broader population because those affected are widely dispersed.”

Building patient registries has traditionally been costly, particularly for rare conditions in which multiple centers are needed to achieve sufficient size. “This pilot study strongly suggests that social networking tools can catalyze community action and that the energy and commitment of affected patients can overcome inertia and reduce registry costs,” says the report.

Women, younger patients, and patients with uncommon medical conditions for which no consensus exists on etiology, treatment, and prognosis might be expected to search more broadly for answers to their questions on the Internet or through other less conventional sources of medical information compared with men, older patients, and those with more common disorders. But the study team found that after the study was underway, they were contacted by a number of persons with SCAD or their family members about clinical and research questions. 

The interested parties were not members or were aware of the original Internet networking group, which led the team to believe that they had heard of the SCAD research from a variety of sources, including specific Internet search activity, personal blogs, Facebook, “word of mouth” through other SCAD patients, and Mayo Clinic Web sites. “This suggests that the inherent interconnectivity of the Internet, combined with a strong drive to acquire hard-to-find health information, can be leveraged even more extensively in the future,” says the report.

Lessons from the Mayo study are prompting the team to expand and “to recruit eligible participants via standard methods as well as through communication with this and other heart disease-based social networking sites. 

“Ultimately, we aim to provide a higher-powered, descriptive database including prospective biospecimen and DNA collection, physical and mental well-being assessment of participants, and comparisons with age- and sex-matched controls. With collaborating centers, we plan to develop a prospective trial to further guide short- and long-term treatment because, as demonstrated by our cohort and others, significant variability exists in the short- and long-term management of SCAD.”

Social Media Patient Recruitment Success Story

At-home clinical trial services are a relatively new niche market. A quick search brings up only a few vendors. One, Medical Research Network (MRN), is based in the United Kingdom and has only recently announced it would establish a presence in the United States by opening up an office in Raleigh, NC. Another UK-based company, Illingworth Research and Research Nurses Ltd, offers a home care agency with a research component; and Coram, primarily an athome infusion service and specialty pharmacy distribution company, also contracts with sponsors to visit trial patients in their homes or work places. 

“Sponsors are just beginning to wake up to the benefits of going directly to the patients,” says Nicki Norris, CEO of the Chicago-based 

, one of the oldest companies in the group. They also extend their reach by contracting with home health agencies globally.

 about why and how the trend for at-home clinical trial services is finally catching on and its impact on retention and recruitment. 

   The company was actually founded in 2003. Our founder worked in both clinical trials and in home care. We’ve really been perfecting our process ever since. There are a lot of moving parts and a lot of people involved in this kind of service. So having a process, the metrics, and the support to make it all work is incredibly important.

   Has your concept changed from then until now? 
 

   Yes, and it has to do with market changes; our understanding of what is necessary; and how we provide it. 
 

 Tell us about the effect of the market changes.
 

 Before the economic pressures of 2007 and 2008, drug development tended to protect its clinical trials and its research people. In the aftermath, players in the marketplace have had to open up more and be willing to look at new ideas. In addition, the FDA is placing stricter requirements on how a trial should be done. One of those in particular has to do with getting a representative patient population or getting an intent-to-treat pool that is similar to the pool that will actually have the drug used on it. 
 

Typically, there are populations that take part in a clinical trial and there are populations that don’t, for a lot of reasons. When you try to get a representative sample of the population in your clinical trial, you have to do some things differently. To get the trial to those people at-home service helps. 
 

  Could you expound further on how bringing a trial to the patients aids the sponsor with recruitment and also retention issues? 
 

  Say you’re a sponsor and either the study itself or the trial design, or the patient population you’re appealing to presents a difficulty. It can be as simple as needing adults to go to a site, 20 days in a row, twice a day, and even if they’re active, that’s a real pain over 20 days. And so the challenge can be in the design; or it can be the patient population; or it can be the geography of the patient population. In short, enrollment can be challenging. 
 

 How then does an at-home service make sense? 
 

 Rather than designing the study for the efficiency and the convenience of the researcher at the trial site, the sponsor can include an in-home or alternate site service in their study. It shows they are really taking into consideration the needs and the convenience of the subjects. It doesn’t need to be for the entire trial. Typically, it’s a complementary service that focuses on visits that don’t require a physician; visits that are a simple blood draw done by a nurse, but it can end up being a tremendous advantage and time-saver to the patient. For the more sophisticated visits that might require an MRI or some sort of instrumentation that can’t be taken into the home, you can have the patient travel to the site. This then becomes an incentive and it will attract more to enroll in the trial.

 It is likely that the nurse or clinician going into the home creates a bond between the patient and the caregivers. This, in turn, appeals to the subject, makes him or her feel more involved and cared for, and helps them to stay in the study. 

 Can you tell me why home-care service is just catching on?
 

     Sponsors are being forced to think about outsourcing, about mobile trials. I just spoke at a conference, and there were several people there that said: “Wow, I didn’t even know this existed.” They just didn’t think about it. 
 

   In terms of retention rates, do you have data that indicates the success of at-home trial services? 


   There’s a retention study on our site (

) that shows the drop out rate for patients who used home care. I believe it was 3%, and for patients who didn’t use home care was like 63%, and on average the study looked as if had a 24% drop out rate, which is pretty close to average. But when you go behind the numbers one step further, you see the differential was convenience. We have data that demonstrates in key studies where our services were able to make trial participation more convenient, patients did enroll, and it changed the timeline for enrollment, which obviously results in time and money for the sponsor. 

Likewise, there are case studies where some patients chose to stick with only visits to the site. While some patients chose to use home care. There is a radical difference between the two groups in retention or drop out rate.


  Where are your services offered worldwide? 
 

   We are a huge contracting organization, with subcontracts with about 250 accredited home-health agencies in the United States, Canada, UK (England, Ireland, Scotland), Spain, Italy, France, Germany, Netherlands, Belgium, Sweden, Denmark, Poland, Switzerland, Czech Republic, Austria, Israel, and Australia. The company works on 40 to 50 studies at one time, mostly for big pharma and large CROs. We typically contract with whoever is running the study. If it’s the biotech company, the pharma company, the CRO, any of those, and we develop our services very much for an individual study, and once that contract with the sponsor is set up for the study, then we go into action with the sponsor, with the lab, with the pharmacy, all the people involved, and we develop exactly how our services will be delivered, how they will be used, what kind of clinician is needed, and how the clinician will be trained. 
 

    Earlier we were talking about what has changed in your operation. Can you think of anything else?

   We’ve been doing a lot of work on the at-homes service’s value to the site. Sometimes sites are reluctant, from a financial perspective, to get into the home care situation, and yet one case study shows that some sites elected to use home care, some sites did not. But the ones that elected to use in home services, i.e., made it more convenient for the patients to have many of the visits in their homes, it enrolled three times more than the other sites. 
 Another study, concerned a rare disease and they were covering patients in 15 states. So we were able to facilitate that obstacle by going into homes all across the United States. 

Recently I was at a site summit in Florida focused on principal investigators. And all I had to do was say the word "snowbird," and these people were all over me. Right now snowbirds leave for Florida for six months of the year, ordinarily they would have to be disqualified from their trials, but with our service we could follow them to Florida. So, in the end we’re bringing together four things: detailed project management skills, clinical trials knowledge, nursing, and home care services.