The same technology that entertains kids can be used as a topographic aid for medical researchers

(Alameda, CA) is using computer-generated imagery to help find tumors, not just a fish named Nemo.

Its Living Image Software 3D Analysis Package, which works with Xenogen's IVIS Imaging system, uses a noninvasive technique to image tumors and other biological processes in living bodies in real time. Clinical applications include being able to measure how a tumor reacts to a drug by seeing how it changes size and shape over multiple readings. 

There are three steps in the imaging process. First, the person (or animal—it works on any living body) ingests a bioluminescent reporter, which will "tag" a specific process to be studied. 

Next, the body is scanned with a laser. The software creates a topographic model of the body. A series of pictures is taken at different light wavelengths, from 560 to 660 nanometers, to capture the "glow" of the tagged tumor.  

Using the different pictures combined with the 3D model, Living Image creates a three-dimensional map of the bioluminescent reporter. It's a bit more complicated than an X-ray, but it will allow tissue to become as easily readable as an X-ray film of a fractured bone. 

LifeTree's virtual filing cabinet offers a trusted third party for companies that have a lot of electronic data

(Temecula, CA) ICTM electronic data capture and analysis platform generates a lot of data. Its eClinical suite offers many more tools for collecting and using that data most efficiently, with metrics and trial management options.

But all that data isn't going to have a safe home on your desktop in an "important stuff" folder. That's where the company's LifeTreeHub comes into play. It's a standalone customizable portal for collecting and storing all the clinical trial documents a multisite, multileg, multidimensional study can generate, from protocols and regulatory documents, to medical licenses and enough CRFs to wow the FDA. And it can all be digitally signed, for added security. 

LifeTreeHub holds more than just CRFs, though. All the Web-based messaging between site and sponsor and clinician can be saved as well, which tells the story of how the data was collected. And LifeTreeHub serves as a virtual meeting site, too. 

 (Temecula, CA) family of companies, providing supplies and services to the health care and life science industries. 

Now you don't have to be an expert in order to read or create sophis-ticated data graphs and charts

(Somerville, MA) has steadily added features to its DecisionSite visual analytics application. The newest addition to the application allows for importation of data from SAS, Insightful S-PLUS, or R Open Source into DecisionSite 8.1.

The new framework also enables users to integrate with other life science programs, from SciTegia, InforSense, MatLab, and even the ubiquitous Excel. A Computational Services function lets users choose to implement DecisionSite's statistical program, or stick with their own in-house method. 

DecisionSite 8.1 was introduced in March, featuring improved data access, better Windows integration, more functions for its Poster feature, and beefed-up security measures.  

All of this leads to a more intuitive way of recasting your information into graphs, displays, and charts. Trends and values that would be buried in a sea of numbers now leap off the screen. Plus, Spotfire's Guided Analytics program makes it possible for nonstatisticians to run algorithms and analyze data without a stats person holding their hand. 

Articles

eShowcase

The media and the politicians had a field day recently, blasting biomedical researchers for decade-old studies that used foster children as "guinea pigs" to test AIDS drugs. Subsequent review of these programs by local and federal agencies reveals that most investigators followed research rules and ethical standards. But the ready charges of "exploitation" and "shameful" behavior leveled by observers reveal that the public is all too willing to believe the worst of clinical trial sponsors and investigators. These developments also indicate how poorly people understand the challenges involved in conducting clinical studies, especially for children. 

Pharmaceutical companies are under pressure to underwrite studies to provide information on appropriate dosing and use of drugs in young patients. Yet, sponsors are subject to attack because such studies often carry risk. The clear need for special protections and precautions when studying drugs in children have generated extensive rules and procedures governing pediatric research. But policies are often unclear, and unanticipated problems can lead to difficulties. 

The foster children "scandal" involved efforts to provide AIDS treatment trials for children while also collecting information on appropriate use of new AIDS cocktails for young patients. The researchers generally followed the rules for enrolling youngsters and protecting their rights, which then were based on policies adopted in 1983 by the Department of Health and Human Services (HHS) under Subpart D of the "Common Rule." These allow institutional review boards (IRBs) to approve pediatric studies that adhere to basic requirements for informed consent and oversight so long as the research does not involve "greater than minimal risk" to study participants.  			

If the risk is more than minimal, the IRB still may approve the study if it determines that the: 					

risk is justified by anticipated direct benefit to subjects

anticipated benefit from the study is at least comparable to alternative treatments

study is likely to yield generalizable, vitally important knowledge about a disorder or condition.

HHS also may approve studies that fail to meet these criteria if experts determine that the research addresses a serious problem affecting children's health or welfare and meets basic ethical principles. Because the AIDS trials in question offered sick children access to new antiviral treatments, the physicians organizing these studies believed that participation did provide direct benefits to subjects, despite the risks. 

Carrots & Sticks: Two Ways FDA Has Encouraged Ethics			

The researchers maintain that it would have been "unconscionable and unjust" to exclude children in foster care from this opportunity for life-saving treatment. They are now thoroughly disheartened at being attacked for what they consider altruistic efforts to obtain critical care for very sick youngsters. The studies included children from conventional families, and did not single out foster children as easily accessible subjects. However, many of the 2000 babies born infected with HIV each year in the early 1990s were poor, minority children and ended up in public and private child welfare agencies, including state foster care programs. The AIDS trials began at a time when scientists were starting to document the efficacy of AIDS drug cocktails for adults, so the National Institutes of Health (NIH) offered support for studies on what treatments could save the lives of young HIV-infected patients. 

The point of controversy is who provided consent for foster children that participated in these trials, a question that involves complex legal issues. Children generally require parental consent to participate in clinical research, But in some cases, guardians and other parties may provide consent for children without parents, including those who are "wards of the state." The state laws that govern foster care, however, vary considerably regarding clinical research participation. Some states forbid any involvement, some have no special policies, and some allow participation with oversight by an independent advocate (see sidebar "Policies for Prisoners"). 

State and federal agencies are reviewing how these studies were conducted, who participated, and whether appropriate consent and oversight policies were followed. Witnesses from HHS and the medical research community testified at a hearing last month before the House Ways and Means Subcommittee on Human Resources, which has been involved with foster care issues. They said that current government policies adequately protect children in medical research, and that drug testing on children is critical to ensure proper care for sick youngsters. Members of the committee seemed to feel that further action was not warranted, but held off final judgment pending the results of investigations by HHS' Office of Human Research Protections (OHRP) and state agencies. 

The allegations regarding exploitation of foster children largely ignored extensive efforts to establish and update ethical standards governing pediatric research over the past 30 years. The research community has long recognized that informed consent raises special challenges when children are involved, and that additional safeguards are needed to prevent even the appearance of unethical behavior. Various committees and research ethics boards have addressed these issues, and the growth in pediatric clinical trials over the last decade has reinvigorated these efforts. 

Congress called on the Institute of Medicine (IOM) three years ago to review federal regulations and policies governing pediatric research and issue recommendations for change, particularly regarding informed consent, payment related to children's participation in research, and IRB responsibilities. The resulting report on "Ethical Conduct of Clinical Research Involving Children," published in March 2004, called for more detailed guidance from OHRP and the Food and Drug Administration (FDA) to help IRBs interpret rules governing children.  

In particular, the IOM panel recommended clearer definition of "minimal risk," the threshold for requiring increased safeguards and heightened oversight of pediatric studies. One aim is to reduce differences between FDA and HHS policies on topics such as when parental consent might be waived. The IOM report also urged IRBs to include pediatric research experts on their panels when evaluating pediatric study protocols, and to adopt explicit written policies on reimbursement of families with children participating in research. It encouraged all government agencies and private researchers to adopt the Subpart D rules governing children, which have been implemented primarily for studies funded by NIH or that fall under FDA's purview (see sidebar "Carrots & Sticks"). 

The HHS Secretary's Advisory Committee on Human Research Protections (SACHRP) already was working to update and clarify terminology related to pediatric research, and moved to incorporate the IOM recommendations into its deliberations. One objective is to define more clearly when a child may participate in a study that involves more than minimal risk and offers little direct benefit. This may relate to the age of the child, whether risks are comparable to those encountered in daily life or routine medical care, and whether the study addresses conditions of such "vital importance" to warrant approval of a more risky study protocol. 

At the April 2005 SACHRP meeting, the panel approved recommendations of its Part D subcommittee for clarifying a number of issues related to assessing risk in pediatric trials. SACHRP requested that HHS issue further guidance reflecting its analysis of how investigators and IRBs should deal with domestic and foreign studies that involve slightly more than minimal risk.  

If a riskier study offers the prospect of direct benefit to subjects, SACHRP proposes that approval depend on whether potential harms are minimal and similar to alternative approaches. When a study offers no prospect of direct benefit but is likely to yield generalizable knowledge about the subject's disorder, an IRB should determine that risks still are fairly low, that interventions won't produce much pain or discomfort, and that the resulting information is of "vital importance" for addressing the disorder.  

SACHRP also is encouraging IRBs to seek higher level review by HHS of complex studies that do not easily meet approval criteria. OHRP issued guidance last month on what protocols IRBs should submit to HHS for further review. 

View from Washington

Recent events highlight the need to clarify rules and policies for pediatric studies.

Protecting the Children

ICH/GCP guidelines, the Declaration of Helsinki, and the recent European Union (EU) laws originating from Directive 2001/20/EC are the currently accepted gold standards of Good Clinical Practice (GCP) for research in Europe.

 The importance of the suitability of investigators and the quality of facilities at clinical trial sites has for the first time been given legal recognition in these laws. The Detailed Guidance text of the EU Directive states that information on the qualification and training of the principal investigator in GCP or experience obtained from work with clinical trials and patient care must be sent to the ethics committee (EC) for their approval of this person in such a role.

 In addition, the EC must also approve the quality of the facilities (including the availability of adequate resources, personnel, and laboratory facilities) at clinical investigative sites. 

 Photography: Comstock   Illustration: Paul A. Belci			

The process and discipline of the clinical trials environment are not for the faint-hearted, and any idea that the ethical, scientific, and practical dimensions of clinical trials can simply be grafted onto a clinical setting without the specialized personnel and appropriate infrastructure is an error. Investigators and their teams are responsible for the conduct of the most fundamental acts performed in clinical trials: giving adequate information to study participants, getting informed consent, the administration of experimental medication, toxicity surveillance of these participants, and the production of credible, quality data. 

There is increasing complexity of study design. Sponsors of clinical trials have constraints (regulatory and financial), and expectations (studies must often respond to efficacy, safety, pharmacological, quality of life, and adherence questions, all in one protocol). There is therefore a need for efficient clinical investigative teams who have technical, administrative, and organizational skills to deliver a quality product in an efficient and timely manner.  

Clinical trial protocols originate from pharmaceutical companies or from the noncommercial sector; i.e., they are developed by clinical investigating teams or by national/international collaborating investigators or research organizations. With investigative sites receiving protocols from such diverse origins, there is need for an adequate number of professional team members experienced in research rules and practice. These members evaluate the ethical, scientific, and practical acceptability of studies at the investigative site prior to their submission to the EC. 

Investigative sites are already graded by sponsors on a number of parameters: 					

adequate personnel with training and experience

In addition, investigative sites should now be able to demonstrate quality practices with job descriptions for study personnel and standard operating procedures for all activities performed in the clinical trial process, for instance the process of obtaining informed consent from study participants.

According to new EU law, investigators who themselves wish to coordinate noncommercial academic interventional trials must assume the responsibilities of sponsors of these studies with the consequent administrative, financial, and legal obligations.

Figure 1. Study coordination at clinical investigation sites.			

The coordination of today's clinical trials has become a complex and professional activity. Figure 1 illustrates the multiple partners involved in the smooth running of a clinical trial. There needs to be collaboration with other departments within the institution in which the study is being conducted and with companies subcontracted by the sponsor for their specialist contribution to the trial process. Examples of such include central laboratories, study drug suppliers, interactive voice response systems (IVRS) via telephone or the newer interactive Web response systems (IWRS), clinical research organizations (CROs), and couriers for the transport of medication or biological specimens. 

Coordination of these processes requires organization of personnel and facilities in order to respond to the needs of study participants, and the pressures from sponsors as well as compete in the present day clinical trials arena. 

The biggest single investment and necessity at any clinical investigational site is personnel. Competent, committed and professional staff members are needed in order to meet the high ethical, scientific, regulatory, and practical requirements of clinical trials. 			

The principal investigator (PI) assumes overall responsibility for the conduct of the study. In accordance with new EU law, this person may also need to take on the administrative and legal responsibilities as sponsor of academic noncommercial studies. 			

A dedicated research physician would be solely responsible for the enrollment and follow up of all patients participating in clinical trials. 			

Study participants might be referred by their treating physician to the research physician who could be responsible for: 					

giving detailed information on the study to the participant 

determining the eligibility of participants

medical follow up of participants during the study and review of examination/test results 

safety surveillance with decisions on biological retests and the (dis)continuation of the study medication if appropriate.

Serious Adverse Event reporting, though this activity is not exclusive to a research physician.

Study participants would be seen by the research physician at the screening, baseline, and follow up visits of the study (and unscheduled toxicity visits if necessary). In parallel, they could continue to see their treating physician (who initially referred them to the research physician and the research team) at regular intervals, and at the end of the study the patient will then continue to receive care from their treating physician. (This scenario could be used for participants of Phase II, III, and IV studies.) 

The advantage of a dedicated research physician in addition to the treating physician is that it provides some degree of a solution for physicians with potential difficulties in reconciling the dual roles of investigators and carers of their patients.

The research physician may be the most appropriate person for the supervision of case report form (CRF) completion. Another repsonsibility is reviewing and summarizing the multitude of The Council for International Organizations of Medical Sciences (CIOMS)/Dear Doctor reports arriving daily at investigative sites for the other members of the research and clinical teams.  

The job of site coordinator requires a serious talent for flexibility. Apart from saying that a person of the medical or paramedical profession may hold this position—it is often a research nurse—there is no end to the diverse activities which the site coordinator may orchestrate, e.g., clinical activity, training, standard operating procedures, job descriptions, contacts with monitors, organization, delegation.

The role of research nurses/research technicians can simply be summarized as the practical translation of the protocol to the bedside or the clinic setting. Research nurses/technicians are most often responsible for the first-line practical running and management of the study with diverse roles as carer, patient advocate, and study administrator.

 There are very specific acts which are restricted to the profession of nursing—blood drawing and the administration of medications. Many of the other roles can be carried out by other paramedical professions, such as dieticians, laboratory technicians, or pharmacy assistants.

These activities can include though are not restricted to: 					

seeing study participants during the study follow up visits:

								–explaining the study procedures and the timing in which these procedures must be performed

				–counselling on adherence to drug regimens

				–appointment management of the study follow-up visit and procedures

				–adverse and serious adverse events/reaction reporting

				–quality source documentation of all data during the follow-up visits

				–instructions to study participants on diary card or questionnaire completion

				–simple encouragement to the patient/participants who have to adhere to protocol requirements and who in many cases also have an acute or chronic illness. 					

participant screening and enrollment logs 

study drug management (ordering, accountability, temperature surveillance of storage areas, and the security of the storage areas)

Feature Article

European law now gives prominence to the suitability of investigators and the quality of facilities, two important clinical trial issues.

Standardizing EU Investigative Sites

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.

 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.

 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 investigators

 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."

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. 

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. 

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

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."

 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. 

 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. 			

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 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. 				

 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: 

, MLS CIS, is a medical consultant within Global Enrollment Optimization, Eli Lilly, (317) 277-7621, email: 

*To whom all correspondence should be addressed.

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," 

3. S. Zisson, "Anticipating a Clinical Investigator Shortfall," 

4. L. Scheible and M. Pozsgai, "The Virtual Training Process," 

Virtual tools and processes are a key way to decrease costs while increasing quality.

The Virtual Revolution (The Time Is Now)

For pharmaceutical and biotech companies wishing to operate on an international basis, a clear understanding of the different regulatory requirements across countries is critical. With the regulatory requirements constantly changing in different countries, however, keeping up to date is no easy matter. An important development in the European Union (EU) has been the adoption of the new EU Clinical Trials Directive (2001/20/EC),

 which will affect all companies wishing to undertake clinical trials within the EU and has thus attracted considerable attention. The two primary objectives of this directive are to provide a more harmonized and structured European regulatory framework, and to ensure the safety of patients enrolled in clinical research. 

 Photography: Comstock, Photodisc    Illustration: Paul A. Belci			

Since its accession to the EU in 1986, Portugal has played an active role on the European stage, and was one of the first member countries to adopt the Euro currency in 1999. The pharmaceutical industry is considered a key sector by the Portuguese government, and in 2002, it publicly announced its desire to stimulate domestic industrial growth while encouraging international companies to base their businesses there.

 Around 130 pharmaceutical companies operate in Portugal and employ nearly 11,000 people.

 Health- care spending has nearly doubled since 1995, and the country has become an important pharmaceutical market.

 The emphasis on health care has also seen Portugal grow in importance as a center of clinical research, as pharmaceutical companies encourage physicians to gain more experience with their products. 			

The steady growth in clinical research is certain to be enhanced by Portugal's ongoing implementation of the Clinical Trial Directive legislation, which will ultimately streamline the submission approval process and running of clinical studies in the country, and significantly improve timelines to competitive levels. 

Unlike the outgoing system in which ethical approval is obtained followed by regulatory notification, the new law establishes the necessity of obtaining  authorization from both the Competent Authority (INFARMED)

 and ethics committee (EC) in order to conduct a clinical trial. Such authorizations can be submitted in parallel. 

The directive made provisions for a two-year transition period in order for it to be incorporated into national law, and one further year (until 1 May 2004) for final implementation. However, in Portugal as with some other EU member states, the directive timelines were somewhat protracted. 			

The legal text of the directive was implemented into the national legislation (Lei No. 46/ 2004) back in August 2004. However, the required guidelines for procedures have yet to be introduced, including the establishment of necessary regulatory and ethics infrastructures in order to apply the principles set out in the new law. Until recently, INFARMED implemented a transition period whereby clinical trial applications were submitted in a hybrid format. Now, INFARMED is receiving CTAs for full review, rather than notification. The transition period essentially involved following the current procedure of initially seeking ethics approval and then notifying INFARMED of the authorization together with a submission of the essential documents (including the EudraCT application form) as stipulated in the national EudraCT checklist. Incidentally, during this transition period, no additional national documents were required. 

EudraCT, established in keeping with the European Directive, is a database of all interventional clinical trials of investigational medicinal products in the EU (registered after 1 May 2004), which records submissions made to both the Competent Authority and the EC. Sponsor entry can be made via the EudraCT Web site

 for the purposes of obtaining the necessary EudraCT identification number, gaining access to supporting documentation such as directives and guidelines, and for completing, saving, and printing electronic forms relating to clinical trial applications, amendments, and end-of-trial notifications. 

Regarding this transition period, INFARMED published a circular (September 2004) declaring that if at least one ethics approval for a clinical trial was obtained before the implementation of the new procedures, that clinical trial would ultimately follow the current transitional system. One important requirement, article 4.1, is that the sponsor must register the clinical trial in the European Database

 and consequently obtain a EUDRACT number unique to that study. 

Prior to the introduction of the new law, Portugal had three stages of monitoring with regard to ethical issues

—the National Council of Ethics for Life Sciences (a consultative body), Centers of Reflection (for bioethical issues), and Health Ethics Committees, which review biomedical research. In order to ensure effective and efficient running of ethics committees, the Portuguese Ministry of Health recently published two official dispatches in which it established a higher grade of review known as the Ethics Committee for Clinical Research (CEIC) and the executive CEIC. Essentially, the executive CEIC will consist of seven members of the CEIC and will meet at least once a week. This new committee, which will be responsible for monitoring Health Ethics Committees in addition to receiving all applications for ethical review, will have the overall power to decide whether a clinical trial is deemed suitable to proceed, and will be responsible for fulfilling review timeline requirements as specified in the directive. For the most part, this board can assign a regional Health Ethics Committee to review the actual clinical trial application in question. In order to begin their activities, these two committees are awaiting final signed approval from the Minister of Health. It is anticipated that all procedures will be operating by mid-2005. 			

With regard to review timelines, under the new system, both authorizations will be issued within 60 days of submission, unless the tested drugs are gene therapy, somatic cell therapy or GMO-containing products. The timeframe for these types of products is 90 or 180 days, if an external group of experts is involved in the application review. However, if the tested drug is a xenogenic cell therapy product, there is no time limit for evaluation. In any case, INFARMED or CEIC can request additional information or clarifications to the application submitted if necessary. This request will be a single event, and there will be a clock stop in the time limits previously stated until the applicant submits the additional information or clarifications. 

One of the main advantages of the new legislation will be that only a single opinion will be given by a central Ethics Committee. This is a notable improvement on the current system where EC submissions have been known to be rather cumbersome at times, with each hospital having different requirements that are not always well-specified. Indeed, there have been cases where a clinical trial had been authorized by an EC of one hospital within a month, only to be delayed due to extra review time required by other regional ECs. For example, one of the main hospitals in Porto had recently been without an EC for a number of months, thereby delaying the approval and subsequent initiation of the study at that hospital. Obviously this is not a common occurrence, but it illustrates how timelines sometimes depend on a variety of different circumstances.  

Furthermore, a centralized EC will avoid particular preferences. Some sponsors and Contract Research Organizations (CROs) favored certain hospitals in the past, not necessarily based on scientific and quality criteria, but rather on the reputation these institutes have for speedy approval processes. It is therefore anticipated that the new timelines imposed by the directive will bring Portugal in line with the other EU member states, and will greatly enhance the country's appeal as a location for conducting clinical trials, a trend that is already on the increase.  

Portugal itself boasts a high number of universities and central hospitals concentrated in major cities such as Lisbon, Porto, and Coimbra, with experienced staff to assist in the studies. Furthermore, most investigators from these hospitals will have significant experience in conducting clinical trials, and also an excellent command of English. Moreover, patient compliance is consistently good, and Portugal has proportionally higher recruitment rates than most other participating countries. One key factor for high recruitment is close follow-up from the very time the protocol is submitted for approval. 			

Another significant development in streamlining Portugal's clinical trial process has been the acceptance of Annex 13, the EU Directive standard guideline for labeling investigational medicinal products. This clearly will harmonize one aspect of how clinical trials should be undertaken and controlled. There had previously been significant differences in labeling requirements within each EU member state. 

INFARMED recently implemented a fees structure associated with the regulatory assessment of pharmaceutical, preclinical, and medical data for applications for clinical trial authorizations. The fees have been estimated to reflect the time and resources required to complete the evaluation of applications and are categorized as follows: €1000 for Phases I to III, €450 for Phase IV, and €250 for bioequivalence studies. 

Law no. 46/2004 also specifies the sponsor, investigator, and monitor responsibilities in the conduct of clinical trials.

 Likewise, it describes the terms of the financial contract between sponsor and site, such as direct and indirect costs, payment schedule, and any other conditions established between the parties. 

During the course of a clinical trial, it may be necessary for the sponsor to make certain amendments to the clinical trial protocol. The new legislation makes provisions for this, and where amendments are considered nonsubstantial—where the scientific basis of the study is not altered or where the safety of the participating subjects is not compromised—only notification to INFARMED is required. In cases where substantial changes are made, CEIC and INFARMED approval will be required. Such approval will be issued within 35 days of submission. If objections are raised to the proposed amendment, the sponsor will have to adapt the protocol in accordance to those objections, or withdraw the amendment under consideration. 

Under the forthcoming legislation, the manufacture or importation of investigational medicinal products (IMPs) are subject to authorization from INFARMED. Such authorization will be valid during the conduct of the study, and must follow good manufacturing practices (GMP). If the IMPs are coming from other EU Member States, such authorization from INFARMED is not required if the batches used are accompanied by the certificates of release issued by the qualified person and follow GMP or equivalent in accordance with the product specifications. 

The new law also describes the type of fines (between €5,000 and €500,000) applicable in case the law is not followed, such as conducting a trial without CEIC or INFARMED approval, or conducting it in different terms than those approved, using IMPs outside the conditions of this law, giving incentives or financial benefits to participant subjects if not allowed by the law, manufacturing or importing IMPs without the appropriate authorization, etc. This system of fines will ultimately protect Portuguese patients in the unlikely event of medical malpractice. Another issue worth noting is that the rate of illiteracy in Portugal is still significantly higher than in some other European countries,

and therefore emphasizes the need for stringent control of ethical practices. 

Portugal has had, for some time now, a sound reputation as a leading player in the pharmaceutical arena. It has successfully positioned itself as an attractive country to conduct clinical research. The country has witnessed a significant increase not only in the number of industrial-sponsored trials, but equally within academic studies. The implementation of the Clinical Trials Directive with its accompanying regulations on good documentation and good clinical practice can only contribute to this upward trend, and will arguably put Portugal at a distinct advantage to a number of other member states that are barely at the early stages of implementing the directive. Considering the current changing environment, it is recommended to verify with INFARMED

 the status of implementation of the new law, and therefore the relevant requirements necessary to obtain authorization for the conduct of clinical trials. 			

, PhD, is with the regulatory affairs department of Chiltern International, 171 Bath Road, Slough, UK, SL1 4AA, +44 1753 216695, fax +44 1753 511116, email: 

PhD, is with the clinical development department of Chiltern International (Portugal), +35 1 93 333 76 06, fax +35 1 21 760 60 96, email: 

*To whom all correspondence should be addressed. 

1. Directive 2001/20/EC Of The European Parliament and of The Council of 4 April 2001. 

Official Journal of the European Communities

europa.eu.int/eur-ex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdf

2. The view-point of Apifarma: The Pharmaceutical Industry as a Strategic Sector. Associação Portuguesa da indústria farmacêutica (APIFARMA) press release. 28th May 2002. (2002) http://

www.apifarma.pt/noticias/?file=noticias_txt&cod=193

3. Pharmaceutical Industry in Portugal. Agência Portuguesa para o Investimento (AIP). The Pharmaceutical Industry in Figures. Associação Portuguesa da indústria farmacêutica (APIFARMA) press release. (2004) http://

www.apifarma.pt/menu/?file=texto&codigo_menu=2103&sel_men=2103

4. O Instituto Nacional da Farmácia e do Medicamento (INFARMED): Apresentação. (2005), http://

5. European Clinical Trials Database: EudraCT. (2005) http://

6. Guideline on the data fields from the European clinical trials database (EudraCT) that may be included in the European database on Medicinal Products. European Commission: Enterprise And Industry Directorate-General. ENTR/CT 6. (2004) http://

7. Portugal RECs and Medical Research. PRIVIREAL. (2004) http://

www.privireal.org/countries/recportugal.htm

www.portcult.com/Portugal.53_illiteracy_in_portugal.htm

The country is in the forefront of European Union nations prepared to explore the brave new world of post-CTD research.

The Clinical Trials Directive in Portugal

The issues surrounding clinical trial transparency and disclosure of information regarding active clinical trials and clinical trial results are in the limelight as never before. 

It started with front-page headlines about the legal actions taken by New York Attorney General Eliot Spitzer against a handful of major pharmaceutical companies suspected of concealing negative trial results of marketed therapies. The issue has since snowballed to include primetime news reports and public outcries for disclosure from patient advocacy groups and influential organizations such as the American Medical Association, the International Committee of Medical Journal Editors (includes 

, and others), and even the World Health Organization. 

Faced with addressing this increasingly public issue, biopharmaceutical companies began taking proactive steps to make more clinical trial information available and easily accessible. Pioneering the industry's effort, Eli Lilly, GlaxoSmithKline, and Forest Labs have all developed online clinical trial registries on their corporate Web sites. The Pharmaceutical Research and Manufacturers of America (PhRMA) developed a registry with pledged support from its member companies. Even the International Federation of Pharmaceutical Manufacturers & Associations, which includes PhRMA and other industry trade groups, has developed plans for action. Most recently, Roche has begun posting what will be nearly 2000 trials for both ongoing and completed studies with a third-party commercial registry.  

Almost all industry stakeholders support disclosure. However, even with all their influence, credibility, and respect in both the health professional and consumer communities, Congress would not let industry figure out the trial transparency issue on its own. Late this February, Congress took serious action. 

Figure 1. Clinical trial disclosure-A rapidly changing landscape.			

On February 28, 2005, Senators Charles Grassley (R-IA) and Christopher Dodd (D-CT) introduced legislation called the Fair Access to Clinical Trials Act of 2005—the FACT Act. The FACT Act calls for the current clinical trials registry located at 

 to be rebuilt and expanded to include information about the results of clinical trials, and to apply to all clinical trials for drugs, biologics, and medical devices. A daunting task, the proposed legislation would require that: 					

Trials must be registered in the data-base in order to obtain approval from a U.S.-based Institutional Review Board

Researchers promptly disclose the objectives, eligibility criteria, sources of funding, and anticipated timeline of clinical trials

Results of clinical trials be available to doctors and patients

Strong enforcement mechanisms, including civil monetary penalties of up to $10,000 per day for sponsors that do not comply. 

This is by far the most aggressive legislative action taken to date to force the issue of trial transparency.  

Biopharmaceutical companies, as well as government researchers, are scrambling to figure out how they will respond if the legislation is ever passed with its current requirements. They are grappling with various challenges: how to collect all of the information internally and get it into the right format for posting; proper staffing for processing, posting, and maintaining this information; combatting competitors' use of detailed information to make adjustments to their own strategy; and last but not least, what results—positive or negative—are statistically significant enough to report. 

Figure 2. Industry adoption takes hold.			

Given the public outcry for this information, combined with the support of professional associations and trade groups, it would be easy to assume that this legislation will not only pass, but be highly effective in getting companies to bare all when it comes to information about their trials. But is legislation necessary? More importantly, will the passing of legislation result in full compliance? If history is any guide, the answer is no.  

In 1997 Congress passed the Food and Drug Administration Modernization Act (FDAMA), aimed at improving transparency of clinical trials information. As part of that legislation, $215 million was appropriated for creation of a public registry of clinical trials. It took nearly three years for the database to be developed and launched, finally going "live" as 

Why it is imperative for government and commercial trial publishers to collaborate in addressing this issue faster.

Applied Clinical Trials-07-01-2005

eShowcase

Protecting the Children

Standardizing EU Investigative Sites

The Virtual Revolution (The Time Is Now)

The Clinical Trials Directive in Portugal

Breaking the Trial Result Disclosure Logjam Now

Agreeing on Pediatric Trials Is No Child's Play

Let's Bring the Trial to the Subject!

Found in Translation