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Sites wrestle with protocol design complexity

Wednesday, March 1, 2017

The growing complexity of protocols is resulting in longer cycle times, rising costs and increased pressures on staff and patients throughout the clinical trial process. Tufts Center for the Study of Drug Development (CSDD) studies have found that the number of endpoints, procedures and eligibility criteria of typical phase III protocols increased significantly during 2002-2012, and have continued to grow. These factors combine to increase costs and burdens on research teams.

“Protocols are definitely more complicated than they were four years ago,” said Raymond Nomizu, director of Finance at Beacon Clinical Research. “There seem to be more procedures, and there is more complexity associated with the procedures and how they are executed. More technologies are being incorporated, which means more logins and more systems.”

CenterWatch’s interview of investigative site personnel found significant impacts from protocol complexity on key activities throughout the clinical trial process, including informed consent, recruitment, participation burden, site visits and data management. Perhaps the biggest challenge for sites is dealing with the time staff need to learn numerous technologies, execute required procedures and manage disparate systems. Sites report feeling overwhelmed by the demand to coordinate large numbers of vendors, portals and software tools.
Informed consent process affects recruitment

Rising protocol complexity increases the time required to screen and obtain consent from volunteers, which increases the work burden on sites. “A screening visit in a complex study used to take maybe two hours,” said Peg Sharp, president and clinical director at Alpine. “Now it can easily take four to six hours.”

Consent forms are longer and more numerous because they cover more procedures and include more technical information. “It’s not uncommon for consents to be 20 to 25 pages long,” said Dr. Cara East, director at Baylor Soltero Cardiovascular Research Center. Trials that include pharmacogenomics studies may also include a separate consent form for DNA/RNA analyses, while another form might be required for consent to receive text messages.

“Having three consent forms at a screening is not uncommon,” said Alpine’s Sharp. High expectations of volunteers as expressed in the consent form can make it more difficult for sites to recruit patients.

Developing a simplified, uniform consent form could streamline the process and save time for site staff. “The FDA has been saying they’d like to simplify the consent, but so far, we’re not seeing that. The sponsors, CROs and IRBs want a lot of legal language, so the consents are getting more complicated,” said Baylor’s East.

She suggests collaboration among sites, sponsors and the FDA to develop a standardized form that covers information common to all clinical research. “Then you could have a separate consent written by the site, just related to the specific study at hand,” said East.

Complexity drains staff time

Performing more procedures on patients extends the length of site visits and increases the time commitment required of staff and subjects. Lengthy visits create challenges for sites in recruiting and retaining patients. “Many people are flexible, but it is almost impossible for someone with a 40 hour/week job to be part of a research study,” said Alpine’s Sharp. “We used to see people on their lunch hour, but we can’t do that anymore. That definitely affects recruitment.”

Alex Wang, site manager for Beacon Clinical Research, cited a recent osteoarthritis trial that lost volunteers because so many imaging studies were required. “They constantly sent patients for X-rays and MRIs,” said Wang. “The patient feels like it’s too much.”

Baylor’s East agreed that volunteers might rethink participation after enrolling, noting that, “Once the patients realize how long it takes, it is hard to retain them.”

Clinical trial complexity also affects the patient reporting process. Protocols increasingly call for the use of electronic diaries, typically on PDAs, that patients can take home. These systems provide benefits such as higher data quality and patient compliance; however, they can create barriers for some older patients who are not comfortable with digital devices. In an overactive bladder study of patients of 65 years and older, Wang said, “A lot of patients dropped out of the study because they could not complete the diary.”

The technology itself may also contribute to a trial’s complexity. “The vendors are selling themselves to the sponsor,” said Deb Shioshita, clinical research coordinator at Alpine Clinical Research Center. “They say, ‘Look what we can capture on this diary,’ and they are actually trying to capture too much information. In one study, the diaries were so complex that the older patients didn’t know how to answer the questions.”

When patients have trouble with diaries, site staff are called on to trouble-shoot technical issues. Jeff Stein, president, Stamford Therapeutics Consortium, agreed that the devices can be problematic for older patients, but he is encouraged by technical improvements. “Overall, the performance level is significantly better than it was five years ago,” he said.

Researchers interviewed also noted increases in the number, length and complexity of questionnaires—recorded using on-site tablets—which require more time for staff and patients. “There are many more questionnaires for the patient,” said East. “Some may take up to thirty minutes to complete. We used to ask a few questions and do a physical, and now we’ve got forty-five minutes of questionnaires. That’s a big change.”

More is expected of site staff in terms of training, experience and headcount. “It’s difficult to hire anyone today without experience. The training and learning curves have gotten so much longer,” said Alpine’s Sharp.

East said, “When the labs, physicals, blood tests, consent processes and data entry systems are more complicated, we have to hire more staff and do a lot more training. All of this complexity affects our startup. It takes longer to write a consent and develop a budget. And there’s a whole lot to go over when we close out because the protocols and data entry are so complicated.”

Data management technology: Challenges and solutions

Managing huge volumes of data has become a major challenge for sites. “We need to centralize this thing,” said Beacon’s Wang. “It is extremely difficult for us to follow up with each vendor.” Different vendors and CROs use technologies that do not communicate with each other, and sites must navigate through a sea of complex systems.

“Technologies that are being pushed to us by sponsors and CROs in some ways can make life easier, but oftentimes—because they are disparate and unrelated—it’s a lot more to manage,” said Stamford’s Stein. “When you have a problem with one, getting somebody who is well-versed at a help desk to solve that problem can be difficult.”

“There is no conductor for the orchestra,” said Alpine’s Sharp. “There is no one we feel we can go to when we have an issue with a vendor.” Sharp noted that sites frequently have trouble obtaining solutions from vendors and monitors for problems with complicated laboratory tests, patient diaries and data systems. She said, “It’s one help desk after another. There is so much technology involved, and things go wrong. That becomes very frustrating for both patients and staff.”

Multiple systems also require additional training and steep learning curves. Wang cited a study in which he tried to outsource electronic data capture (EDC) entry, but the rules for entry were so complicated that the site brought the task back in-house. “It takes longer to train somebody than to do it ourselves,” said Wang.

Despite the complexity they introduce, well-thought-out data technologies can streamline communications among sites, vendors and sponsors, and will hopefully increase investigative site productivity. “Two years ago, we moved to our first electronic regulatory binder system,” explained Stein. “As the industry continues to move to remote monitoring, I now have a way to give our monitors remote access to all of our regulatory documentation.”

A growing trend is industry’s use of electronic source (eSource) document platforms. “The next change we’re making here is moving to an eSource document system,” said Stein. “We’ll be able to give monitors access from anywhere they can get an internet connection, on a read-only basis, to all of our source data.”

eSource technology continues to evolve and holds promise for increased site efficiency, productivity and lowered costs. Stein said, “The next stage, although we’re not there yet, is when my eSource vendor links this system with various EDC systems so that our data can get pushed into the EDC.”

Data entered directly from electronic source documents into EDC systems will avoid human error and change the cost structures around manual data entry and verification. The FDA is promoting the integration of electronic health records (EHRs) and EDCs, and software vendors are working on solutions to integrate electronic source data with EDC systems. If successful, these approaches will have a transformative impact on clinical research. “This is potentially a seismic shift in the industry,” said Stein.

Moving forward

Investigative sites believe sponsors and CROs might be able to address challenges such as lengthier cycle times, rising costs and increased staff pressures by reining in protocol complexity where possible. Many researchers feel protocols require more tests and complexity than needed.

“Some sponsors require a complete physical exam at every visit,” said Alpine’s East. She cites multiple blood pressure checks, blood tests, EKGs that require a sponsor’s machine and complicated processing and shipping requirements for labs as measures that increase staff time and require additional training. “Sometimes sponsors or CROs have requirements that are not necessary. They’re setting up things for us to do that are more complex than they need to be.”

Reducing the time required to execute complex protocols would also help sites recruit and retain investigators, especially when physicians feel the compensation is not commensurate with the time commitment.

“I am starting to see physicians say, ‘No, this is not worth it anymore,’” said Sharp. She noted that removing unnecessary redundancy in various processes, such as filling in multiple screening, informed consent and drug accountability logs, could ease the time burden on sites.

While there is much sponsors could address, sites are looking for better coordination of vendors and a higher consideration of the impact that procedures and technologies have on investigative sites. Even a slight ease to the challenges posed by protocol complexity would bring relief to sites inundated with longer consent times, lower staff availability and an overabundance of technology solutions. 


Barbara Bolten is a consultant and writer providing services to biotechnology, pharma and consulting companies. She has nearly 20 years as a market research professional at Decision Resources and in independent practice with a focus on therapeutics, diagnostics technologies and business strategies. Email bbolten@verizon.net.

This article was reprinted from Volume 24, Issue 03, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>

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