The Virtual Revolution (The Time Is Now)

Several environmental factors have recently emerged that are drastically affecting pharmaceutical research and development. The costs associated with the development of a new molecular entity are increasing. In 2003, the Tufts Center for The Study of Drug Development estimated the development costs at $897 million dollars.¹ Additionally, an increasing number of molecules fail in late-stage development, further adding to developmental costs. This was shown in a Bain and Company article published in 2003 that estimated these costs, including commercialization costs, at $1.7 billion.² What factors are involved with these increasing development costs?

Photography: Comstock, Eyewire Illustration: Paul A. Belci

Market demands for innovative pharmaceuticals to treat unmet medical needs continue to exist and are driven by an ever-increasing aging population. This issue, coupled with shortfalls in the numbers of clinical physicians and their clinical trials staff, increasing market demands for more cost-effective pharmaceuticals as demonstrated in cross-boarder sales, parallel importation, and increasing private and public payer influence are some key environmental factors that are affecting drug development.

New product registrations are increasingly requiring more data analysis for drug approval. In life- threatening illnesses, such as various cancers and cardiovascular diseases, survival data is increasingly required for primary study endpoints. Many trials now have longer patient poststudy follow-up periods, which is extremely important for developing detailed safety and efficacy profiles but which also lead to larger, longer, more complex, and costlier clinical trials to achieve these goals.

When coupled with a shortage of clinical investigators³ and increased numbers of products in development from sponsors, study sites are seeing increased volume in clinical study opportunities. This can lead to the site having less time to dedicate to each clinical trial. The investigative site also has its own issues associated with the execution of clinical research, such as budget constraints, staff shortages, and continuous staff turnover. Shortages of clinical volunteers also compound the challenges associated with effective and efficient patient recruitment, leading to longer trial enrollment periods as well as more complex, global trials—further affecting developmental costs.

All of these factors increase trial timelines, complexity, and costs. Meanwhile, the pharmaceutical industry is being pressured to decrease sponsor research and development budgets and overall new drug entity costs. As a result, more efficient clinical development processes must be injected into the current methodology to help decrease development costs and reduce timelines, while also maintaining high quality. What are some key process options?

The virtual training process (distance learning)

Trial initiation or study start-up training can be a significant and costly challenge for sponsors and clinical sites and networks. Consider the number of individual clinical sites and staff that are often involved in upcoming trials, not to mention retraining efforts for staff turnover once the study initiates. Virtual training processes can offer a significant benefit in any trial, but especially in larger and longer trials being conducted throughout a clinical network or with numerous clinical sites:

"The virtual training process can offer both the clinical sites and the sponsor many advantages, such as training flexibility based on the trainee's schedule, decreased travel, and cost and time savings. These savings are noticed even more as studies progress and staff re-trainings are required due to new site additions and staff turnover."⁴

In [4],how to establish a virtual training process is discussed in detail and described in a logical manner to ensure 21 CFR 11 compliance, proper validation, etc. Even though some time must be spent up front establishing a virtual training process for the sponsor, the benefits for future trials far outweigh the costs.

Secure document repository development

Prompt and secure document access and delivery throughout any clinical trial is extremely important to ensure optimal study communication, patient safety, prompt clinician updates, study timelines, and the maintenance of confidential asset protection. But, just like study training, secure document access and delivery throughout a clinical network or with numerous sites can present significant challenges. Frequent overnight mailings can be extremely expensive and time-consuming, considering the number of participating sites and staff. Confidential asset protection issues rise as more mailings occur throughout the network or sites, not to mention time delays as clinical physicians and staffs await important documents or updates. Secure document repositories, which are essentially secure Web sites, may be utilized to help resolve these issues. Just as with the virtual training process, establishing a secure document access and delivery process will take time upfront to establish a robust process that is compliant with 21 CFR 11 (Electronic Records, Electronic Signatures), HIPAA (Health Insurance Portability and Accountability Act), and internal security policies, and is properly validated. But, the benefits to be obtained from future trials far outweigh the costs.

Depending on how the document repositories are designed, the clinical network staff (PI, study coordinator, floor nurses, pharmacist, regulatory officer, etc.) and sponsor field staff (monitor, medical liaison, etc.) could access a trial-specific, general-access area to obtain approved, general study documents, blank forms, logs, templates, contact information, and study updates. The repository may also be designed to allow for document- or area-level access. The general access area would be created and maintained by a small, select, controlled group (the "sponsor" study team) to ensure proper version control and updated content. A periodic audit process would need to be established to document and ensure updated, proper content and user access. Trial-specific, restricted access areas within the repository could also be utilized by the sponsor study team to distribute and access restricted study documents for sponsor use only, rather than mailing copies of restricted documents to field staff. The restricted access area would be maintained by the same sponsor study team.

All users would access the secure document repositories by use of an assigned username and password. Thus, a robust and validated account management system would be needed for initial assignment, password resets, and account deletion at study closure or if user participation ceases. Security policies such as forced initial password changes, periodic password changes, unsuccessful attempt rules, and timeout periods would also need to be established. An access control list process that would allow the end users to view only their study-specific repositories, which they have received clearance for, would be essential as well.

Various platforms exist for development of an internal solution, as well as numerous off-the-shelf configurable solutions and vendors with secure repository services. The key to proper process development and tool selection is the creation of a needs analysis and then a vendor/tool analysis. These analyses will streamline the repository process development and tool selection. Some of the key parameters to look for in a tool or vendor service is a robust account management process for proper security, a help desk support structure for prompt user issue resolution, user friendly interface, 21 CFR 11 compliance, HIPAA compliance, end user/computer preparation process (Internet connectivity, Internet browser version, etc.), archival process at study closure, and proper validation documentation. The analyses should be performed working closely with the sponsor field staff, information technology, and medical quality assurance to ensure the best choices are made and compliant processes are developed.

Secure document delivery

Another eClinical process to consider developing and utilizing along with document repositories is a fax-to-repository document delivery process. If the process is developed properly, it can allow for cost-effective, secure document delivery that is 21 CFR 11 compliant and does not require extensive end user training or special hardware or software. The end-user would obtain blank forms or templates from the trial-specific, general access area, complete the form as per form instructions (including signature/date, if applicable) and then fax the completed document to the sponsor study team using their standard fax machine and a trial-specific fax number. The process would be secure since the fax call would arrive at a fax server residing behind the sponsor's firewall. Moreover, the fax would be converted to a locked, noneditable format (i.e., .pdf, .tif) attachment and delivered to a therapeutic or possibly trial-specific initial receiving area with controlled/limited access. Then, the study sponsor team's regulatory staff would have "read only" access to open and review the locked document for accuracy and completeness. Assuming that the document is deemed acceptable, the document could then be transferred using an electronic transfer agent to a trial-specific, restricted access repository area for storage and eventual archival. Posting into the restricted access repository area would also allow the sponsor's field staff (i.e., monitors, etc.) to view the approved documents and updated tracking reports to perform their field functions in an optimal manner. This is opposed to calling the sponsor's "in-house" study team numerous times and waiting on hardcopy mailings.

Figure 1. An example fax-to-repository inbound process flow, And Figure 2. An example fax-to-repository outbound process flow.

If the document is deemed to be unacceptable, the regulatory reviewer would then send the unacceptable document back to the sender (clinical site, field staff) along with a cover sheet listing out the issues that needed to be corrected. The locked document and cover sheet would be sent electronically from the initial receiving area back to the fax server, where it would be converted to a fax and delivered to the sender's designated fax. The sender (clinical site, field staff) would review the fax coversheet and document; record any corrections on the "original" document on file; then initial, date, and record a reason for change for each correction. The corrected document would then be faxed back as previously described for review by the sponsor's regulatory staff. Depending on the document type and the audit trail requirement, the sender may complete an entire new document or template to be faxed back for review. The sponsor's monitor would verify all original documents during their periodic clinical site visits. Figures 1 and 2 show an example fax-to-repository inbound and outbound process flow. The advantages of a fax to repository process are many:

• Facilitates sponsor/site communication to global study sites without computer or Internet access

• Prevents numerous mailings, saves staff time, and prevents information update delays

• Increases confidential asset protection

• Prevents scanning of completed documents (for posting into repositories) and saves time

• Saves server storage space, since the locked .pdf or .tif files may be compressed

• Easy and cost-effective to implement and validate.

Another approach is to develop a process that includes eSignature capabilities, thus allowing for document completion and signatures to occur completely online rather than utilizing a hybrid approach as previously described. A completely electronic approach can offer many benefits, but additional validation, testing requirements, and budgetary constraints must be considered as well. Keep in mind that certain "original" completed study documents may be required by the sponsor and thus must be mailed back to the sponsor no matter what eClinical processes are developed.

One final element to complete the sponsor's eClinical tool chest is an electronic data capture (EDC) process. A well-developed EDC process will allow real-time access to data, online trial monitoring that saves travel time and increases trial efficiency, better trial management, and overall improvement in data quality. Numerous articles have been written on the development process to ensure 21 CFR 11 and HIPAA compliance, as well as the validation and testing process and benefits. As stated by an author of a recent article, "Provided that sufficient thought is given to the initial expenditure on planning, training, software, and capital equipment selection, the cost of EDC can be recouped many times over in more efficient and effective project control, leading to faster project completion."⁵ When developing an eClinical process, it is extremely important to work closely with your quality and IT staff to ensure that the process is 21 CFR 11 (ER/ES) compliant, properly validated, and that all procedures and training are developed for all end-users.

Cycle time reduction and productivity impact

Virtual training was initially tested and piloted on a few small trials with up to 10 sites, and was appropriately scaled up to studies that now have well over 1000 investigator sites. Studies completed to date include Phases II–IV. From the onset of using the virtual training process, great care was taken to assure quality of clinical investigator and clinical site staff training, and to ascertain that the new tools and processes did not sacrifice performance as compared to the time-tested live study start-up meeting. Study milestone cycle time was also closely monitored. Finally, any cost savings associated with the process were also monitored.

Cost savings associated with virtual training are meaningless if study quality suffers. Should study quality decrease, the costs associated with mitigating these issues could far outweigh the cost savings achieved through the virtual training process. Key metrics were identified as a means for consistent ongoing measurement of study quality. Data quality metrics such as the number of CRF queries per CRF visit were identified as a meaningful metric, due to the fact that CRF training is a key and complex component of study startup training. Additionally, GCP issues per trial were utilized as a surrogate metric. However, there are additional factors besides training that can affect this metric.

Table 1. Live vs. Virtual: Quality metrics GCP issues and CRF queries.

Table 1 shows metrics from a sample of studies, including completed as well as ongoing studies. Quality data was obtained for studies for the period 1999-March 2005. Five compounds from multiple therapeutic areas were monitored, and studies under each compound were grouped together by phase, size, and number of countries involved in the trials. Studies in red represent trials that were completed using only virtual training, and studies in black represent study training that was completed by only a standard, in-person start-up meeting.

Observations from the CRF Query/CRF Visit Chart include the fact that studies completed using the virtual training process performed as good or better than studies that utilized in-person training. Feedback from investigator sites and sponsor study teams regarding training quality give some interesting insight into these metrics. These include factors such as consistent high-quality presentations from the topic expert, consistency in training and retraining of both investigator sites as well as sponsor staff, the ability for sites to easily re-review training material throughout the study, and site staff who were trained but were unable to attend a startup meeting.

While training has an effect on GCP issues, several factors can also affect this metric. Factors may include other issues such as investigative site clinical research experience, investigator site staffing, general workload, and study complexity, among others. Observations of the GCP metrics include an overall general decrease in the number of GCP issues per site for studies performing similar to those with live training.

In addition to the quality metrics previously discussed, close attention was given to study start-up timeline performance to assure that the tools did not lengthen the study start-up process or negatively influence productivity at the site. The metric chosen to measure the most appropriate portion of the overall trial timeline was from Protocol Approval to Site Regulatory Readiness. Site readiness indicates that shipment of study drug can begin to that site.

Figure 3. Protocol approval to site regulatory readiness and virtual training cycle time reduction, and Figure 4. Historic number of virtual trials and cost savings.

In Figure 3, a sample was taken of U.S.-based trials that occurred from 2003 through June 2004, representing 1287 sites. To obtain an accurate cycle-time representation for each tool, studies that only used a complete virtual start-up were compared to studies that used a complete live start-up. Within each study, the median duration from PA-to-Regulatory Readiness Date of all sites was calculated. This median duration was used to represent the median cycle time for the trial. Each trial median cycle time was then used to calculate the overall virtual time, which was compared to studies not using virtual tools as a means to measure cycle-time impact. The results showed cycle-time reduction of 13% for studies using virtual training, 9% for studies using both tools, and 6% for studies using document repositories.

Cost savings and additional benefits

Virtual training

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The cost of a live study startup can be expensive. Costs associated for a live study startup meeting include meeting planning, travel, accommodations, facility, and audio /video rental. A very large start-up meeting could cost in the hundreds of thousands of dollars. The cost of virtual training tools has dropped from a cost of approximately $30,000 in the late 1990s to below $10,000 today. Cost savings have increased with the increased use of the tool. Based upon the increased use of the tools for study startup meetings, an increase in the number of studies is shown in Figure 4. Sponsor study teams gained confidence in the virtual training tools and then employed less conservative approaches. The number of studies has increased over time, with a strategic shift in 2004 to focus on fewer, but larger, studies. An increasing number of sites were trained in each subsequent year, with cost savings as a result of the virtual training process now running in the millions of dollars and trending upward. These savings have often allowed for the initiation of additional clinical trials and/or decreases in clinical budgets. Again, it is important to reiterate that cost saving without quality is meaningless.

Document repositories

With the use of document repositories and extranet access for clinical investigative sites, several factors are involved in the cost savings and benefits with the use of these tools. One key benefit is real-time access to updated information by clinical sites. Additionally, the secure Internet access affords confidential asset protection of study-related information.

With the cycle-time reduction previously discussed, similar productivity savings can be seen with sponsor staff. The outcome of surveys showed the productivity of sponsor field staff using the tool can save approximately four hours per person per week, while internal sponsor staff has seen savings of approximately two hours per person per week. These figures may vary depending upon individual sponsor processes and to the extent that the repositories are used. The main savings associated with the use of the tools are due to reductions in direct mailings to the site. Additionally, the tools may be used for off-site monitoring of site study binders, regulatory documents, and timely correspondence to the sponsor or site.

The time is now

The time is now for clinical sponsors to establish well-designed, user-friendly eClinical methodologies such as virtual training processes and secure document repositories. The benefits to be gained in higher quality, positive timeline and productivity impacts, increased confidential asset protection, and increased cost savings far outweigh the costs of process development and maintenance. The old clinical research methodologies of holding numerous live meetings that involved frequent travel, sending frequent mass mailings to update site and field staff, and manual completion of hundreds or even thousands of trial documents have become extremely inefficient and unsustainable. The time is now for changes to occur so that everyone—the sponsor, clinical staff, and the patients—may benefit.

Lee S. Scheible,* RPh, is a senior medical consultant within the U.S. Medical Affiliate, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, (317) 276-8405, email: scheible_lee_s@lilly.com. Michael A. Pozsgai, MLS CIS, is a medical consultant within Global Enrollment Optimization, Eli Lilly, (317) 277-7621, email: pozsgai_michael_a@lilly.com.

*To whom all correspondence should be addressed.

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. Gilbert, P. Henske, A. Singh, "Rebuilding Big Pharma's Business Model," In Vivo, 21 (10) 76 (2003).

3. S. Zisson, "Anticipating a Clinical Investigator Shortfall," Center-Watch, 8 (4) 1 (2001).

4. L. Scheible and M. Pozsgai, "The Virtual Training Process," Applied Clinical Trials, 11 (10) 44 (October 2002).

5. O. Wiechers, "The Move to EDC," Applied Clinical Trials, 11 (11) 38 (November 2002).