The Clinical Investigative Site Network

According to a recent 2003 Impact Report by Tufts Center for the Study of Drug Development, pharmaceutical companies now have an average total R&D cost of $802 million per new drug entity and $897 million, if both pre-and postapproval phases are included.¹ Pharmaceutical companies must initiate their clinical trials in an increasingly efficient manner to ensure thorough protocol development, prompt regulatory readiness, high quality, cost-effective study initiation training, accurate and efficient study supply delivery, steady enrollment, quality data collection, monitoring, reporting, timely issue resolution, datalocks, and study closeout. All of these functions must be done within a set budget and timeline.

This is a difficult, multitask assignment that might become even more difficult as the medical industry braces for the aging baby boomers. Couple this with potential investigator shortfalls, stricter regulations, and tighter trial budgets as the industry tries to control drug development costs. What might be a potential option for accomplishing the challenge of developing drugs while lowering costs and decreasing development times?

The clinical investigative site network

Clinical investigative site networks, defined as a group of independent clinical sites based upon specific qualification criteria that function as one entity, may be a new option for offsetting the increase in R&D costs. The networks may differ within and between therapeutic areas. In addition, they may offer a variety of services and have some similarities to site management organizations (SMOs) and contract research organizations (CROs).

Table 1. Regulatory readiness (protocol receipt to study drug shipment-in working days)

The entire network is managed by a central administrative staff, as per set network procedures. The central administrative team often oversees and streamlines financial, regulatory, safety, data management, business processes, quality assurance, and site selection concerns for each trial. Like an SMO and possibly a CRO, the central administrative staff would determine the appropriate number of sites and locations for participation in each trial based on the trial criteria, network needs, and the current trial portfolio within the network. Unlike most SMOs and CROs, however, the clinical investigative network functions as a participating clinical site by performing required trial functions that include financial functions, regulatory readiness, data management, and safety reporting.

In contrast to most CROs, which are often contracted to perform specific sponsor functions, networks require sponsor monitoring. Networks are regionally structured and further divided by disease state. Each region is assigned a lead investigator for the specific disease state based on the investigator's expertise. The investigator serves as a representative on a central disease state committee and as the lead facilitator/communicator for all trials involving that particular disease state being conducted in their region. In addition to the regional lead investigator for each disease state committee, an advisor (primary or principal investigator) functions from within the central network office and facilitates/coordinates the disease state committee. The advisor is responsible for advising, leading, and coordinating the regional lead investigators.

The central administrative staff coordinates all public relations for the entire network. As potential trials are offered to the network, the central administrative staff works with the primary investigator or advisor to initiate a scientific review of the potential study protocol, involving the appropriate disease-specific committee and thus each of the regional lead investigators. If the protocol is approved, then the legal/financial component of the central administration staff initiates contract and budget negotiations with the trial sponsor.

Table 2. Enrollment rates (Network A vs. all other single sites participating in same trial; U.S. only trials)

The regulatory readiness process, including informed consent document (ICD) development and the institutional/ethical review board (IRB) review process, are initiated within the regulatory component of the central administration staff. Networks typically utilize a central IRB for the entire network consisting of proper membership as per 21 CFR 56. Supply shipments such as lab kits, study drug, and case report forms are coordinated by the central administrative staff working with the trial sponsor. Study initiation training is coordinated for all network participants by the central administrative staff. Upon receiving IRB approval, completion of the regulatory readiness process and the study initiation training, the study drug is shipped by the trial sponsor to the network so that enrollment may commence.

Clinical investigative site network benefits

One significant benefit is that the sponsor works through a central administrative staff rather than several clinical administrative offices, reducing the number of contacts and streamlining study communication. Specific clinical processes are coordinated through one central office, reducing the timeline associated with completing these tasks. For example, the contract, IRB approvals, ICD, and privacy content negotiations are streamlined as all reviews are handled by one central legal group, financial group, and IRB, as compared to dealing with multiple clinical sites and committees. Scientific review of the study protocol is also streamlined, since one scientific committee handles reviews with one review process for the specific disease state. A high level of efficiency and quality may be reached due to the consistency associated with a central staff and set processes. Efficiency and quality lead to faster trial initiations and completion, as indicated in Tables 1-3, which were compiled based upon three trials conducted using both the network and single-site models.

Table 3. CRF query rates (Network A vs. all other single sites participating in same trial; U.S. only)

Issue resolution can be streamlined due to the network model. The network quality assurance department helps to ensure compliance and prevention of issue trends by maintenance of network processes, procedures, training, and periodic audits of the satellite sites. Clinical networks often utilize a central study drug/lab kit ordering and delivery system to maximize efficiency. The clinical trial management systems are usually electronically based and are located on the network's secure intranet. The centralized pharmacy process allows for the sponsor to ship initial study drug to only one location, which can minimize overhead for both the sites and sponsor.

Although a clinical investigative network may be more expensive in comparison to a single-site model, this may be due to clinical networks having larger study initiation and per-patient fees to cover the central administrative costs. However, benefits may outweigh the costs if the sponsor considers the number of actual sites that are being initiated for the larger fees, the quality and timeline impact due to better process and staff consistency, and the potential enrollment impact on the study. The clinical investigative network also provides increased exposure for trials that are conducted within the network. This is often accomplished by utilizing network intranet systems, collaborations, and enhanced communication processes through network newsletters and monthly update teleconferences. Another potential benefit of the clinical network is that smaller clinical institutions may have an increased opportunity to participate. The patients and physicians can benefit since more trial options are available.

Figure 1. A section of an example clinical investigative site network trial initiation checklist.

This network model may not always be the most efficient design for every clinical trial, due to the increased time that it takes to establish initial network processes and procedures. Most likely, these trial types will be small, early-phase trials or trials with shorter enrollment periods. The sponsor must consider all of the network benefits and issues as summarized in Table 4.

Key topic discussions

Conducting an initial strategy meeting in the early planning phase may be helpful in understanding the clinical network structure, clinical processes, and how the network differs from the typical single-site model. Using discussion tools, as illustrated in Figure 1, may be beneficial to ensure the right questions are asked at the right time and that detailed minutes are recorded. Key topics for discussion might include regulatory readiness and timelines, including FDA 1572 process, ICD review/approval, IRB structure to ensure 21 CFR 56 compliance, safety reporting, drug accountability, and monitoring (centralized versus decentralized). The use of eClinical processes and tools such as virtual training processes for study start-up training, document repositories for secure document exchange, and electronic data capture might be another important topic. This discussion could help to ensure compliance with 21 CFR 11 and that the end user computers are properly prepared for upcoming tool use. In a recent

Applied Clinical Trials

article, Carpenter stated, "Initial 21 CFR 11 compliance assessments of a site's systems should begin during the site selection process."

²

Conducting key topic discussions early in the planning phase may help to ensure that well-defined clinical processes are established with the investigative network.

Table 4. Clinical investigative site networks

Summary—Formation of an alliance

The sponsor should consider the probability and the benefit of conducting additional future trials within the network, and thus the benefits of developing an alliance between the clinical investigative network and the sponsor. The formation of an alliance agreement will facilitate a commitment from both sides, and lead to a true partnership so that both parties feel true ownership and will work together to develop the most efficient and compliant clinical processes. The alliance agreement should list specific high-level objectives like compliance, ethics, quality, commitment, process development, level of participation, communication, and "high level" timelines and metrics. Experience has shown the resources spent in the early stage of the alliance formation and on procedure and process development have paid off throughout the life of the alliance, with increased process comprehension and compliance, reduced process issues with each trial, improved quality, faster trial initiations, and shorter trial timelines, while also reducing overall costs.

References

1. Tufts Center for the Study of Drug Development, "Impact Report: Post-Approval R&D Raises Total Drug Development Costs to $897 Million," 5 (3) May/June 2003.

2. J. Carpenter, "21 CFR 11 Compliance at Investigator Sites," Applied Clinical Trials, 12 (7) 35 (July 2003).

Lee S. Scheible,* RPh, is a senior medical consultant with the U.S. Medical Affiliate, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, (317) 276-8405, email: scheible_lee_s@lilly. Donald R. Russell, MS, is a clinical plans manager with the U.S. Medical Affiliate, Eli Lilly and Company. Karen J. Brinkman, BSN, RN, OCN, is a clinical operations team leader with the U.S. Medical Affiliate, Eli Lilly and Company.

* To whom correspondence should be addressed.