Sites and sponsors find common ground to accelerate study start-up
Collaboration between sponsors and sites improves process
Whether you're on the sponsor side or the clinical site side, you're probably acutely aware of two trends in clinical research: Contract negotiation and study start-up are big stumbling blocks in the advancement of research. The good news is that in spite of the challenges, both sides are talking about it and looking for common ground and solutions that work for everyone.
Sponsors need good performing sites to conduct their trials, but historic disconnects between work and pay may be driving many qualified investigators away from research. "Averages we've come up with from our database indicate that from 2000 to 2006, 44% of all PIs who filed 1572s only did one study," notes Daniel Ulrey, MBA, president and CEO, Midwest Clinical Support, Inc., Rolling Meadows, IL, at the 44th Annual Drug Information Association meeting in Boston, MA.1 "In 2006 and 2007 Phase II and III studies, 36% of sites enrolled one or no patients. Only 26% of sites enrolled 100% of the requested patients."
Retention rates were little better at 50% of those enrolled. According to Ulrey's research, which is based on standard infrastructure costs, a clinical site would need a retention rate of 65% to be profitable.
Given those numbers, Ulrey says, "it's my opinion that they found it too tough, they weren't paid enough, and got out."
As bleak as those numbers may seem, they suggest that qualified investigators are in high demand.
For example, notwithstanding all the attention India has received from sponsors — to the projected tune of $1.5 billion by 2010 — they're in much the same situation. "To fully capture $1.5 billion by 2010, India will need 50,000 clinical professionals," says Ulrey. "India only has 10,000 available today and is training only 3,000 more annually. Of those, only three of 10 are getting the training required by CROs."
Add to that a 40% attrition rate and 20% who relocate abroad to cash in on Western pay scales (which translate into as much as five times what they can earn in their home country), and the situation is "no different in China, Pakistan, India, or anywhere else," explains Ulrey. "It will take them till 2018 to meet that demand curve."
One of the reasons often cited for trials moving abroad has been the large potential subject populations available. Ulrey posits another perspective, one based on increased performance. He suggests that here in the United States it's not a shortage of subjects, but a shortage of qualified physician investigators. He offers staggering statistics on the reluctance of physicians to participate in clinical research.
Industry averages on payables and timelines
How long do you have to pay your bills? How long does your employer take to pay you? Credit cards have a 30-day cycle, with payment due about two weeks later. Many utilities require payment for the coming month.
These are common arrangements — but not so common at clinical trial sites, says Ulrey. There, according to his research, the average receivable timeline is 141 days — that's almost five months. Further evidence of frustrating delays: On average it takes 73 days to reach site agreements for Phase III studies and 8.4 months lapse between original site contact and first subject in.
All the while, budgets have gone down an average of 12% annually from 2000 to 2007, right along with performance: Over the past 20 or so years, the time and money required to bring a new drug to market has increased from 5-7 years and $500 million in 1995 to 10-12 years and upwards of $1.5 billion today.
Sites and sponsors: Common objectives
These very challenges are leading sponsors to re-examine their relationships with sites in an effort to assist with study startup and enrollment.
Many have begun this re-examination with a hard — and realistic — look at budget negotiations. According to Scott Jensen, MBA, manager, Global Clinical Budgeting and Contracting, Eli Lilly and Company, Indianapolis, IN, effective and fair budgets are based on a set of budget objectives and assumptions common to both sponsors and sites:1
1. Promote clarity. "Protocols can be difficult to translate into specific work activities," Jensen says. "The important aspect is to secure a mutual commitment so we can begin to move things forward.
"Assumptions are really the basis for pricing out a clinical study," Jensen explains. "Unfortunately, due to work pressures we all get hurried to put things in place and get studies up and running."
2. Negotiate fair compensation. In determining appropriate budgets, notes Jensen, it's not just a matter of how many subjects and site visits. Several measures must be taken into account:
- How complex is the study?
- How difficult will it be to meet the inclusion/exclusion criteria?
- How many procedures will be performed?
- How much time will be necessary?
"Some studies," Jensen concedes, "are just more complex." (See list of patient accrual assumptions and common cost drivers, below.)
Patient Accrual Assumptions
Common Cost Drivers
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"The devil is truly in the details," Jensen says. "If you rush through this process, it's very easy to make a mistake — underestimating or overestimating what will be required to conduct the study."
For this reason, Jensen says, "It's very important to understand how the study is priced out. This includes recognizing not only the patient care elements, but also the administrative responsibilities, and aligning both parties around these assumptions and expectations. The last thing you want is to start a study with a known budget deficiency."
Commitment to these common assumptions and expectations is especially important, Jensen acknowledges, because sometimes legitimate issues do come up. "Whether you have amendments or adverse events, sometimes you do need to make adjustments," he explains. In these cases, documentation is essential: "You have to be able to justify what you're doing in the eyes of the FDA."
Documentation also may be a determining feature of the payment schedule. "For most big pharma companies, payments are tied to key milestones," notes Jensen. "So it's going to be critical to understand this going into the study."
Lastly, Jensen stresses that efforts must be made to ensure that the reimbursement structure does not interfere with clinical decision making. "Ultimately, our goal is to produce good clinical data," he explains. "We don't want payments to lead to overutilization, underutilization, or inappropriate utilization. The reimbursement schedule should not affect safety or quality of care."
3. Focus on performance and accountability. The current environment is challenging everyone to be more efficient, but Jensen contends that cost management is only one aspect of this challenge.
"The only way we're going to meet these challenges is through teamwork and a focus on performance and accountability," Jensen says. "To get to that level of success both sides want, we have to find ways of improving quality and speed, which will lead to efficiencies.
"By increasing clarity, transparency, risk-sharing, and accountability, we will also be able to share in the reward."
Acknowledging the limitations of metrics
One area of focus that may help create more realistic measurements for assessing clinical trial performance is a re-tooling of key study performance metrics. "Protocol approval to first subject in has been used historically as a key metric in assessing performance," says Hassan Movahhed, MS, vice president, Clinical Development, Elan Biopharmaceuticals, United States, as part of a panel discussion on best practices for accelerated study start-up at the 44th Annual Drug Information Association meeting in Boston, MA.2 "Sometimes there's a rush to get that first subject in, you get there, and you have a big mess."
"There needs to be more accuracy in performance predictions," adds James Kremidas, Global Enrollment Optimization, Eli Lilly and Co., Indianapolis, IN.2 "It may be much more telling to measure a few key metrics — protocol approval, first subject in, and last subject in — and analyze these metrics over time to create benchmarks."
"Speed doesn't necessarily equal quality," notes Movahhed. "Moving faster isn't the only goal. We want to be predictable with timelines and with quality."
With regard to enrollment, there appears to be a greater understanding of what it takes to meet enrollment goals. "There's an acknowledgement that the effort required to enroll the first 25% of subjects is not equal to the effort required to enroll the last 25% of subjects," notes Javier Revuelta, PharmD, PhD, MBA, senior director, head of Clinical Operations Europe & Asia, MDS Pharma Services, Spain.2 "It's important to take this factor into account when developing initial predictions."
Realistic expectations: The road to success
Agreeing upon realistic expectations — and being honest about the ability to deliver — may be the key determining factor in producing successes for both research sites and sponsors.
"Sometimes feasibility studies are completely useless," notes Revuelta. "There's no synopsis, no drug name, no fees, but we must predict number of patients required and time needed for ethical review. We can end up with data but no true information."
And sometimes, notes Kremidas, it all depends on who you ask. "Feasibility for a PI is a scientific question," he explains, "but for a CRA it's an operational question.
"We can't use metrics to game the system," he adds. "We have to look at overall cycle times and approach this working as a team with sites."
For Kremidas, part of this teamwork approach involves the development of master service agreements for high-performing sites and streamlining processes. "We have done this successfully in oncology," he adds.
Dedicated start-up units are another best practice for study start-up. "At MDS, we have dedicated start-up groups," notes Revuelta. "They guide clinical teams and project managers with multidisciplinary teams."
References
- Investigator budgets: Impact on patient enrollment and retention. Presented at the 44th Annual Meeting of the Drug Information Association; Boston, MA; June 23, 2008.
- The keys to establishing best practices for accelerated start-up. Presented at the 44th Annual Meeting of the Drug Information Association; Boston, MA; June 23, 2008.
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