Subject recruitment and compliance remain a daunting necessity of the clinical trial process, often requiring sponsors to spend excess amounts of time and resources. 

Presently, companies designed specifically to address such issues that provide in-home and alternate-site health care services have emerged within the clinical trial industry and are sparking international interest. 

These unique services allow investigative sites to have tests conducted at a subject's home rather than require the subject to be on site. "By making study participation more convenient, more patients are more willing to participate," said Gail Adinamis, founder and chief executive officer of Clinical Resource Network (CRN), a leading provider of these services that's based in Deerfield, IL.  

Case Studies: CRN Services Effect on Subject Compliance and Trial Timelines 

Now, after proving successful in the United States, CRN is expanding into the international research market. Adinamis explained to 

that the initial plan was to expand only within the United States, but because of increasing proposals from foreign countries, the expansion plan was altered to include the international market. 

Though it had already done business in Canada and the UK, within the last year, CRN's services have reached over 20 new countries, most of which are located in Europe. "There's a popular demand for our services on a global basis; six out of nine are global requested services," Adinamis said. 

When deciding which countries to establish its services in, Adinamis said, "we look at it from a variety of attributes, including clearly defined regulations, clinical infrastructure, and even tax perspectives."

Companies around the world are trying services like CRN's because it proposes a solution to one of the biggest challenges in clinical trial studies. Adinamis explained that "once the ideal subjects are enrolled, there is an average 20% to 30% dropout rate." 

In an effort to prevent these dropouts from affecting the trial, "designing protocol sponsors will over enroll and have 20% to 30% overage." Taking such precautions can lead to wasted resources, while a lack thereof can result in a lengthened trial, and "over 95% of studies fail to meet the target timeline," Adinamis added. 

Gail Adinamis, founder and chief executive officer of the Clinical Resource Network. 

Homecare services can become even more critical in trials that focus on subjects with debilitating diseases such as Alzheimer's, or rare diseases. Subjects with "rare diseases, which affect less than 200,000 people, are remotely scattered and they typically have to fly them and their caregiver to the investigative site," Adinamis explained. "The cost to fly is far more expensive and patients having to travel can be challenging." 

When sponsors choose to utilize these services, they instruct CRN on what services will be needed on a subject-by-subject basis. Once a specific subject's requirements are clear, CRN reaches out to the appropriate professionals within its network of over 3000 prequalified, licensed, and accredited home health care agencies and over 10,000 individual clinicians. 

CRN's program managers are then responsible for training a primary and backup nurse on the GCP and study-specific requirements. The nurses then conduct the services, complete the necessary documents, and forward them to the investigator site. 

In order to efficiently integrate its services into the international market, CRN uses "country program managers who are familiar with the local culture, language, and regulations. We did a lot of planning upfront to understand the local requirements, so we're well prepared for specific countries," Adinamis said. 

"Our homecare project management services are available 365 days a year, 24/7," Adinamis added. Beyond providing personal homecare services for the individual subject, CRN also offers pharmacy and supply services. 

As CRN has sprung full force into the international market within the last year, it has no plans on slowing down. Continuing on its expansion into the international market, Adinamis told 

 that in the following year, CRN will be developing its services in Australia. 

As a result of the tremendous growth it has experienced recently, CRN has been included in the 2000 Inc. 5000 list,

's list of the fastest-growing privately held companies in the United States. CRN was also recently certified by the Women's Business Enterprise National Council (WBENC).—

Articles

News

Specialty at-home and alternate-site testing services offer solution for subject recruitment issues.

At Home Testing Offers Solution

Getting patients and doctors into clinical trials has become the most delay ridden aspect of the drug discovery and development process over the past 10 years. Patient and investigator recruitment and retention are often cited as the most costly and time consuming aspects of trial operations.

  However, there is good news for managers seeking new ways to facilitate the overall clinical trial process, especially enrollment of subjects. Simulation exercises, made possible today by customizable decision support technologies and well-defined predictive analysis strategies, can help clinical trial managers cut costs, reduce risk, forecast outcomes, and increase efficiency. 

Increasingly, pharma companies are turning to simulation—a merger of strategy, analysis, and technology that enables them to run through virtual scenarios of their major initiatives. A new application of this technology is in the critical area of clinical trials. The end tools allow the user to forecast the resources needed, predict and adjust the anticipated costs, establish realistic goals, measure and mitigate their risks, and in the end make better business decisions. For example, the solution can be used in conjunction with existing or expected recruitment data to help predict how patient recruitment sites will perform based upon a predetermined protocol using a set of input templates.  

Photography: Getty Images    Illustration: Paul A. Belci			

In this context, the protocol is a study plan on which all clinical trials are based. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. By definition of the U.S. National Institutes of Health, a protocol describes the following: 					

What types of people may participate in the trial

The schedule of tests, procedures, medications, and dosages

Decision support technology can run multiple replications of many different scenarios that take into account the clinical trial process's variability and complex resource interdependence. These scenarios generate realistic data on how a company's subject recruitment process will perform. This includes enrolling recruiting sites, setting up training sites, getting subjects recruited, dosing them, seeing them through the entire cycle, and then closing out the clinical trial. 

Companies that want to implement a simulation strategy must first determine if they have a need. To gain the greatest benefit, a company engaging in simulation should have more than one clinical trial per year. It should also be a relatively sizable mid cap or a larger firm that runs clinical trials frequently to justify the time and effort required for implementation. 

Second, trial managers should communicate with other key participants and decision makers early in the study to determine if there is a specific need to complete a trial on time and within a certain budget—and what those parameters are. It is critical that trial managers talk not just to the doctors and scientists conducting the study but also to the senior management in the company and other trial managers. 

The next step, data evaluation, has a significant impact on how simulation is carried out in the clinical trial. Companies and their consultants or technology providers must review the available portfolio data and determine if it is sufficient to support full predictive analysis. It's important to know how long a particular site takes to get up to speed, when it's fully trained, when it starts enrolling subjects, and what possible delays could arise. 

Many times individual sites have their own data, or the pharmaceutical company has collected data from past experiences. Relevant information includes site type, delays to recruitment of the site, delays to training of the site, different cycle times, and more. The accuracy of the data regarding delays to site qualification and rate of subject enrollment is critical to the success of the trial. The risks of using data that is based on estimates rather than actual results can be mitigated by expanding the bounds of the distributions that are used for these entries in the simulation. 

If a company and site have no data of their own, consultants will create a template of similar sites in the same country and give it a suitable range of variability to accommodate margin of error. For example, if you were to look at doing training and site recruitment in Germany, the parameters, regulations, and cycle times that are specific to that country would need to be considered in order to achieve the most accurate results possible. Both approaches share the same goal: to ensure data is accurate and dynamic so that companies can arrive at realistic and actionable answers. 

Distributions are then built around the data and put into a decision support model. They capture a company's designated recruiting process and timeline and ensure that it fits within the boundaries of a given tool set. 

Clinical Trial Milestone Summary Table			

Once the protocol is prepared and approved and the data fully entered, testing begins in one of two ways. The "push" method involves putting the information in the simulation technology tool and running multiple scenarios to determine project deadlines. This produces site enrollment and subject recruitment curves with future confidence intervals. 

The "pull" method, on the other hand, tells managers the best set of inputs for reaching a given goal and achieving cost savings. First, project leads define all possible sites and related costs. Then they run a genetic goal-seeking algorithm optimizer to blend the effects of site qualification requirements, screening volume and losses and startup and subjects costs. 

This step helps determine the optimum test center combination for a given protocol and often at the lowest possible cost or the earliest required date since these two measurements are often mutually exclusive. It also takes into account the delay time from site selection until the start of subject enrollment due to regulatory requirements for each site (see Figure 1). 

The information is typically relayed on a scaled up recruitment prediction curve that pinpoints the cycle's milestones and goals. This includes first subject first visit, first dosage final subject, final dosage, and the end point event or the point when the final subject exits the study population. 

Decision support technology can be expanded to include the subject screening protocol for most therapeutic areas. This option is helpful in cases where data is available on the different criteria that can result in subjects being disqualified from participating in the clinical trial. This data can be combined with the projected patient screening volume to projected subject enrollment in the trial. The technology then tracks this population of randomized subjects until they complete the designated requirements for treatment and monitoring (see Table 1 and Figure 2). 

Simulation will provide the maximum value in cases where there is a choice regarding the selection of trial site enrollment. Simulation can aid in identifying the group of sites that will best achieve the trial objectives for subject enrollment using both the trial completion date and the trial cost as the objective functions of the optimization process. Once the enrolling sites have been chosen and the trial is underway, this tool can continue to provide value by combining both actual and projected subject enrollment to ensure that the projected schedule is met or exceeded. 

If problems occur and result in subject enrollment falling below expectations, simulation can aid in minimizing its impact on the overall trial. The comparison between actual and projected enrollment will not only make it possible to identify problems at an early stage but such a comparison can also can be used to evaluate the best option for recovering from the problem, by evaluating whether it would be helpful to supplement the original list of enrolling sites. 

Effect of Nonproducing Test Centers on Subject Enrollment			

While simulation is used most effectively from the beginning of a clinical trial, it can be implemented at any stage of the trial. Once the enrolling sites have been characterized for subject enrollment rates, simulation can be used to create a subject enrollment curve along with a projected completion date. This curve can be used to continue to track the progress of the trial and function as both an early warning indicator and a corrective action method in a manner similar to that noted earlier. 

In short, the practice of simulation in clinical trial subject enrollment enables managers to capture test center variability in a single cohesive summary. And it brings a single flexible tool to companies that can track and address any situation that arises in the organization, granting greater visibility over the entire project lifecycle. 

Companies also gain tomorrow's history today through predictive analysis. Simulation can help identify counter intuitive events in their systems, such as sites that offer high volume enrollment but may not be the best choice if they have lengthy qualification and enrollment startup delays. It can also provide an early indication of when and where trials are derailed. This awareness can be combined with additional simulation scenarios to quickly identify options to help the trial recover and complete its objectives with a minimal disturbance to the original targets. 

In addition, the program's results help trial managers produce more realistic, accurate goals. This makes the trial's management case much stronger before senior executives and increases the chance that the trial will receive support. It also facilitates cost avoidance, where companies can recognize a project's viability early in the process. If it won't be economically feasible to reach the subject recruitment goals in any realistic time frame, management can sunset the project and save valuable resources. 

Lastly, adopting simulation strategies provides risk mitigation. Companies that are new to the clinical trial process or embarking on a trial for a disease that they've never targeted before are presented with the opportunity to gather realistic, projected answers to some of their most pressing questions: 					

This, in turn, can alleviate the risks of choosing the wrong site and subjects, underestimating the clinical trial's time frame, and going significantly over budget. 

Even at its best, the site and subject recruitment process is highly variable and risk-ridden. Clinical trial simulation helps pharmaceutical companies find the right answer the first time around—and much more quickly than traditional methods. When implemented effectively, clinical trial recruitment initiatives such as trial simulators significantly reduce timelines and meet recruitment targets ahead of schedule. And that means the product is one step closer to hitting the marketplace and achieving rapid return on investment, the ideal outcome. 

1. Cutting Edge Information, "Clinical Operations: Accelerating Trials, Allocating Resources & Measuring Performance" (2006), http://

www.cuttingedgeinfo.com/clinicaltrialbenchmarking/index.htm

 is vice president and general manager at ProModel Life Sciences Solutions, 7540 Windsor Drive, Suite 300, Allentown, PA 18195, (860) 443-8882, email: 

Feature Article

The use of computer simulation models to improve both site selection and subject recruitment.

Simulated Strategies for Better Trials

The global expansion of pharmaceutical production and clinical research has put pressure on the FDA to step up its oversight of foreign drug development and production. The scandal over contaminated heparin imports has spurred Congressional investigations and proposals for legislative reform. And with thousands of clinical trials taking place all over the world, policy makers want to know how well FDA and sponsors can ensure the validity of foreign data and of investigator compliance with good clinical practices (GCPs).  

Biopharmaceutical companies are eager to launch studies in these regions to gain access to larger numbers of patients with untreated conditions. Local clinical trials also can facilitate entry into fast growing Asian markets for medical products. But the rapid expansion of research in China, India, and other newly industrialized nations—and variations in national legal requirements related to informed consent and ethics board oversight—create challenges for ensuring appropriate protection of patients.  

One FDA response is to clarify its requirements for conducting foreign clinical studies intended to support a market application in the United States. FDA will accept data from overseas trials not conducted under an IND (investigational new drug application); the agency even has approved a few drugs solely on foreign studies. About half of all trials submitted to support pivotal studies include at least some foreign data, pointed out FDA Senior Advisor for Clinical Science David Lepay at DIA's annual meeting in June. And reliance on non-U.S. data is likely to rise along with growth in overseas trials. 

To ensure that foreign data will be accepted by the agency, FDA published a final rule in April, which goes into effect in October, clarifying that studies must follow GCPs, including approval by an independent ethics committee or institutional review board (IRB). This policy replaces an earlier requirement that clinical trials must follow the ethical principles described in the 1989 version of the Declaration of Helsinki—a controversial change that has raised questions about U.S. support for international ethical guidelines. 

The rule describes what information sponsors should provide about investigators, research operations, protocol design, and trial oversight to demonstrate adherence to GCPs and an ability to ensure data quality. FDA emphasizes that sponsors cannot just certify compliance with GCPs but have to document how they meet requirements. FDA seeks to be flexible, to minimize duplicative information requests, and to accommodate multinational studies with sites in and outside the United States. 

Separately, FDA is supporting efforts to harmonize procedures and policies for conducting international clinical trials for medical devices. The Global Harmonization Task Force (GHTF) for developing and updating medical device regulatory requirements has issued a proposed document outlining general principles of clinical investigations for medical devices. FDA published a notice in July seeking comments on the GHTF approach and how it differs from U.S. policy. 

Under its final rule on foreign clinical studies, FDA notes that it retains the right to validate clinical research data in the United States and abroad through on-site inspections. FDA normally audits several pivotal study sites listed in an application, but the growth in overseas trials makes it difficult for the agency to keep up the pace. FDA has doubled the number of international GCP inspections for drugs from less than 50 in 2000 to more than 100 last year. These foreign inspections account for about 10% of FDA's 1024 bioresearch monitoring (BIMO) inspections in 2007. That's still a paltry number, and it includes very few site visits in Asia despite a surge in research activity in India and China. The number of overseas GCP inspections is expected to grow in 2009 due to rising political pressure plus increased resources to support FDA oversight of food and drug imports. 

FDA's familiarity with political and scientific issues affecting foreign drug development is slated to gain from on-the-ground regulatory offices in critical parts of the world being established under commissioner Andrew von Eschenbach's "Beyond our Borders Initiative." The first in-country operation will be in China, followed by similar offices in India, Europe, Latin America, and the Middle East. 

FDA hopes to open offices in Beijing, Shanghai, and Guangzhou by year end with a relatively small staff of 13. They will conduct some site inspections, but primarily will work with local regulatory authorities to better track enforcement activities, to become more informed of legal and political issues affecting drug regulation, and to further acquaint Chinese regulators and manufacturers with U.S. quality standards and enforcement policies. 

India is next in line, and FDA is negotiating to establish offices in New Delhi and Mumbai to oversee the vast volume of drugs and active pharmaceutical ingredients (API) exports and to better monitor burgeoning research activity. More than 500 registered trials are being conducted in India, up from about 50 five years ago. Major research centers in India have established IRBs and emphasize compliance with GCPs as well as policies set by the U.S. Office for Human Research Protections (OHRP).  

Despite additional funding to support more foreign inspections and overseas operations, there is broad agreement that FDA will never have enough resources to catch everything. This reality is building support in the United States and abroad for collaborations among regulatory authorities to leverage resources and reduce redundant oversight activities. 

FDA has more than 70 cooperative arrangements with foreign counterparts that facilitate information sharing on inspections and safety. Some 30 confidentiality agreements permit disclosure of more detailed reports and data. Such information can help regulators learn more about foreign facilities and research activities in making decisions about where to target foreign inspections. 

Another collaboration will test the benefits of better coordinated foreign drug manufacturer inspections. FDA is teaming up with the European Medicines Agency (EMEA) and Australia's Therapeutic Goods Administration to consult on inspection schedules and reports, initially for active ingredients manufactured in China and India. If successful, the program could expand from APIs to drug products and other activities.  

Third-party certification provides a further approach for more efficient use of regulatory resources. FDA seeks to accredit government and independent entities capable of verifying that certain operations or products comply with U.S. standards. Similarly, accreditation of clinical investigators, research sites, and ethics committees in the United States and abroad has been discussed by OHRP, FDA, and research organizations as a way to streamline oversight while ensuring compliance with research standards. 

FDA also is expanding support for regulatory "capacity building," particularly to broaden understanding of ethical standards involved in clinical research and the importance of local ethics boards in protecting the rights of human research participants. More capable regulatory authorities in other regions can further bolster FDA efforts to ensure compliance with GCPs. 

Although information sharing and joint inspection activities can make the foreign inspection process more efficient and productive, neither FDA, EMEA nor other regulatory authorities are ceding their right to make independent enforcement decisions regarding any research site or facility. The hope is, though, that joint oversight will breed confidence in the approaches and decisions of colleagues, explained EMEA Head of Inspections Emer Cooke at the DIA annual meeting. These collaborative activities eventually could lead to increased reliance on each other's inspections, Cooke suggested, adding that "cooperation, not competition" is the key.  

View from Washington

FDA is conducting more inspections to ensure that foreign clinical research meets GCP standards.

Global Trials Draw Regulatory Scrutiny

Electronic medical records (EMRs) have been considered a panacea for cutting down on medical errors, streamlining recordkeeping, and delivering quality care to patients by health care providers, medical technology companies, and even the president of the United States.

  They are also seen as a boon to clinical research by assisting in matching cancer patients with the right clinical trial,

  aiding in cost effective subject recruitment, and rapidly identifying adverse events.

  However, not everyone agrees that EMRs are ready for prime time. 

In a recent practice improvement study, researchers looked at 50 primary care centers to evaluate the effect of EMRs on outcomes for treating diabetes. The study found that primary care centers using EMRs were less effective in treating diabetes than centers using standard recordkeeping systems. The researchers noted that there were significant differences among commercially available EMR systems, including the amount of training and technical support available.  

Photography: Getty Images    Illustration: Paul A. Belci 

, concluded that "a high level of support for EMR implementation will be required" to meet the federal goal of EMRs for all Americans by 2014 while preserving and enhancing the quality of medical care. This analysis has promoted a lively discussion on the journal's Web site, with comments containing alternate viewpoints.

Sponsors of clinical research are responsible for monitoring the progress of the investigation.

  In addition, medical device sponsors are responsible for having written procedures for how they will monitor the study.

  When monitors and quality assurance auditors visit clinical sites, they are confronted with a number of concerns about EMRs. These concerns fall into three broad categories:  

Privacy: How does the Health Insurance Portability and Privacy Act (HIPAA)

  impact a monitor's ability to review EMRs?

21 CFR Part 11: How does FDA enforcement of Part 11

  impact a sponsor using EMRs as source documents?

Data integrity: Do EMRs provide the same level of data integrity that a paper record does?

A look at federal laws, regulations, and guidance documents as well as two case studies, provides answers to some of these questions and establishes a framework for GCP-compliant monitoring and recordkeeping. 

With the advent of HIPAA in 1996 and the Privacy Rule regulations of 2002,

  many institutions began limiting access to EMRs. Clinical investigators, however, are required by FDA to maintain "adequate and accurate case histories."

  The principal GCP guideline, the ICH Guideline for Good Clinical Practice (E6), states that a sponsor specify that the investigator and institution shall "provide direct access to source data/documents for trial-related monitoring."

The Privacy Rule requires that an individual participating in research provide signed permission or "authorization" before records may be accessed for researchers. This issue can be effectively dealt with in the informed consent form (ICF) that a research participant signs prior to any research related activities. The FDA-required elements of informed consent include a confidentiality clause that notes the possibility that FDA may inspect the records.

  ICFs routinely include that sponsor representatives may review the records. However, this one clause isn't sufficient to meet the requirements of the privacy rule. The ICF must also explain that a participant may withdraw from the study, the duration of the study, and the participant's signature and date. Each of these elements is necessary to meet HIPAA requirements. However, it is important to note that some institutions require a "stand alone" authorization that is separate from the ICF. In addition, some states may also require stand alone authorization. The sponsor needs to be aware of local regulations and policies. 

The National Institutes for Health have also published a guidance document on Clinical Research and the HIPAA Privacy Rule.

  These guidances indicate that it is not necessary to have a stand alone HIPAA disclosure. Compliance with the Privacy Rule can be accomplished with an appropriate ICF. 

The Privacy Rule reinforces the importance of the informed consent process in clinical trials. It is important that the research participant be given a copy of the ICF in the language used during the consenting process. The Privacy Rule emphasizes that the consent authorization "must be written in plain language."

  If the investigator and sponsor prepare an adequate ICF and conduct an effective informed consent process, there is nothing in the Privacy Rule that prevents the monitoring of any medical record, including EMRs, even if the EMR is part of a larger record that includes nonresearch related health information. That is no different than the paper-based medical chart that monitors have been reviewing for decades. The question of privacy is resolved with appropriate disclosure in the ICF. 

There have been few issues as confusing as the FDA regulation of electronic records and electronic signatures under 21 CFR Part 11. This confusion was compounded when some FDA inspectors probed the Part 11 compliance of hospital EMR systems. This continued even after FDA scaled back enforcement of Part 11 in the August 2003 Part 11 Scope and Application guidance document.

One of the results of industry's Part 11 concerns is that sponsors began taking a closer look at the EMR systems in use at clinical sites. Sponsors wished to ensure that their data was being collected and recorded in a system that FDA would find acceptable. It is important to note that FDA has not asserted jurisdiction of medical institution EMR systems for compliance with Part 11. Instead, they issued the guidance document, 

Computerized Systems Used in Clinical Investigations

  This document is essentially protocol specific and does not mention EMR systems at institutions. 

The concept of protocol specific compliance is very important. FDA regulates drugs, medical devices, and biologic products and not the practice of medicine. A case history can be used to illuminate this point. 

A clinical study coordinator was approached by a sponsor with a lengthy questionnaire regarding the institution's compliance with Part 11.

  The sponsor wanted a detailed response from the institution's IT department. The IT members were not familiar with Part 11 and adhered to different technical standards. The questionnaire was not necessary because the FDA does not have jurisdiction over an institution's recordkeeping, only the investigator's records for a specific protocol. If the electronic recordkeeping system is specific to the protocol, it should follow the May 2007 guidance. If the institution's recordkeeping system is used for the practice of medicine, then it is not in FDA's jurisdiction. Essentially, sponsors should make sure that their own systems are compliant for their specific protocol, not the institution's. However, this does not mean that Part 11 should be ignored. In fact, the May 2007 guidance is instrumental in helping to ensure that records generated by an EMR system are GCP compliant. There is a continuing need for quality standards for recordkeeping of clinical research. 

An example is when it is the intention to print EMRs and use them in a subject case history for a clinical trial. Then, it should be done in a manner consistent with FDA guidance. The guidance document allows for a certified copy to be made of an electronic record. Using certified copies is one way of maintaining data integrity of EMRs. The guidance requires a dated signature to attest that the EMR has "all of the same attributes and information as the original." 

Developing quality standards is best done at the beginning of the study. Sponsors must familiarize themselves with the recordkeeping system of each clinical site and work with investigators and study staff to establish consistent documentation of protocol required data. When using EMRs it is necessary to establish the source document and how the integrity of that document will be maintained. 

A look at another case study can show us why.

  A clinical site printed out an EMR and used it as a worksheet or study "source document" in a clinic chart. Several copies of the printout existed with undated and unsigned handwritten annotations. There were three or more versions of the same intake summary or operative report, each with different data.  This is in direct conflict with the recordkeeping maxim of Attributable, Legible, Contemporaneous, Original, and Accurate (ALCOA). This resulted in an audit finding that was discussed with the investigator and study staff. It easily could have resulted in an inspectional finding listed on a FDA Form 483 Inspectional Observations during an FDA inspection. 

Sometimes it is necessary for a monitor or auditor to travel to a specific workstation at a location other than the investigator's offices to review an institution's EMRs. That should be determined at the beginning of the study and built into a monitoring or auditing plan. Case report forms (CRFs) need to be compared against source documents. If the source document is a printed EMR, then the monitor needs to periodically verify the accuracy of the printed version. First, it should be a Certified Copy with a dated signature. If the source document is the EMR, then the monitor needs to have access to the EMR to do the comparison with CRFs. This is particularly important for review of adverse events (AEs). If the EMR is not reviewed, then review of AEs is not occurring. 

The inherent problem with EMRs is the fact that they can be changed over time. The need to document certain data at a certain point in time can be addressed with the "certified copy." For example, if you want to document adverse events at study visit three, then you need to have some means of documenting data entry on the date of visit three. 

Here again we encounter the concept of a protocol specific electronic record. If the clinical investigator wants to use an EMR to document a protocol required activity, then a certified copy is a useful tool. However, if the source document remains in a medical center's EMR system, while the sponsor and FDA have the right to review it, there is no way to guarantee that the record has been changed since the protocol required activity occurred. It is a difficult situation that sponsors and investigators are grappling with. 

Electronic medical records and computerized systems are now a part of daily life, but EMRs still have a way to go before they can actualize everything that's expected of them. In the mean time, sponsors can take steps to ensure the protection of each participant's privacy and the integrity of data captured on EMRs. 

 1. G. Bush, 2006 State of the Union Address, The White House Web site, http://

 2. J.W. Goldwein et al., Abstract No. 6626, 

, 2007 ASCO Annual Meeting Proceedings, Part 1 Vol. 25, No. 18S (June 20 Supplement) 2007: 6626. 

 3. M. Mowry and D. Constantinou, "Electronic Health Records: A Magic Pill?" 

 4. J.C. Crosson et al, "Electronic Medical Records and Diabetes Quality of Care: Results From a Sample of Family Medicine Practices," 

, Title 21, Part 312 Section 56(a) (U.S. Government Printing Office, Washington, DC). 

, Title 21, Part 812 Section 25(e) (U.S. Government Printing Office, Washington, DC). 

 7. U.S. Department of Health & Human Services, Health Insurance Portability and Privacy Act of 1996 (U.S. Government Printing Office, Washington, DC). 

, Title 21, Part 11 (U.S. Government Printing Office, Washington, DC). 

, Title 45, Parts 164-168 (U.S. Government Printing Office, Washington, DC). 

, Title 21, Part 312.62(b) (U.S. Government Printing Office, Washington, DC). 

11. Food and Drug Administration, "ICH E6 Good Clinical Practice: Consolidated Guidance, Section 4.9.7, 

, Title 21, Part 50 Section 25(a)(5) (U.S. Government Printing Office, Washington, DC). 

, Title 45, Part 164 Section 508(c)(2) (U.S. Government Printing Office, Washington, DC). 

Guidance for Industry: Part 11 Electronic Records; Electronic Signatures—Scope and Application

Guidance for Industry: Computerized Systems Used in Clinical Investigations

Shedding light on common EMR concerns about privacy, government regulations, and data integrity.

The Ins and Outs of Electronic Medical Records

National and international public opinion polls document that public confidence and trust in the clinical research enterprise has eroded steadily during the past decade. But despite widely publicized controversies that have damaged the public's trust and confidence in the credibility of stakeholders in the clinical research enterprise, their desire for better health and well-being has not diminished. The public has demonstrated remarkable tolerance for mistakes. As such, there is a unique but closing window of opportunity for the clinical research community to build on this foundation to restore public confidence and trust. 

A number of polls indicate consistently that general public support for medical and health research remains strong and has not changed significantly during the past decade. Two HarrisInteractive polls, conducted between two and five years ago among more than 1000 American adults, found that eight out of 10 people believe it is "very important" to "essential" that all new drugs and treatments are tested on human beings in clinical trials before they are approved for general use. 

A 2004 poll conducted among 1000 Americans by Research!America, a lobbying group representing academic institutions and foundations, found that 94% believe that medical research is important for the economy and 68% perceive clinical research as having great value for public health. Polls conducted in Western Europe show similar levels of positive attitudes about clinical research among the public. In a 2004 survey among 225 Europeans, 90% considered clinical trials important and 60% acknowledged that clinical research plays an important role in advancing public health. This survey and those sponsored by Research!America were conducted largely among adults who have never participated in clinical trials. 

Although the public clearly holds positive attitudes about the general importance of clinical research, they distrust professionals who oversee, manage, and support that research. The public also distrusts organizations responsible for ensuring patient safety and the patients who are willing to associate with clinical research professionals. Consider the following: 					

In national polls conducted in 2006 among 1000 U.S. adults, only 14% of respondents said that they consider clinical trials "very safe," and 48% consider clinical trials "somewhat safe" (CISCRP).

A 2007 poll found that 27% of U.S. adults don't trust the Food and Drug Administration and only 31% believe that the FDA is effective at ensuring safety (HarrisInteractive).

Nearly half of Americans (46%) say they don't trust Capital Hill officials who govern regulatory oversight and drug development processes (HarrisInteractive).

Four out of 10 Americans (42%) don't trust pharmaceutical and biotechnology companies and feel that they have failed to serve consumer interests (HarrisInteractive).

A January 2008 survey found that nearly half of American adults (45%) don't trust research sponsors to inform the public quickly when safety concerns about a drug are uncovered (Kaiser Family Foundation).

Half of white respondents (49%) and 73% of minority respondents reported that it is "very likely" or "somewhat likely" that they might be used as guinea pigs without their consent. And more than one out of four minority respondents (25%) and 22% of white respondents believe that their doctors would expose them to unnecessary risk in clinical trials (Braunstein et al., 

One out of four American adults believes that doctors and study staff are primarily motivated to recruit volunteers for money and selfish interests (HarrisInteractive, 2002).

Public distrust in clinical research professionals has tainted the public's view of clinical research volunteers. National and international polls both show that a large percentage of the public considers research subjects to be risk takers, motivated to find clinical trials because they are either greedy or desperately ill. 

For example, eight out of 10 Americans believe that study volunteers are taking a gamble with their health, according to a 2002 HarrisInteractive poll. A 2006 survey conducted by the Center for Information and Study on Clinical Research Participation (CISCRP) among 900 U.S. adults found that one out of four believes people choose to participate in clinical research because they are "very sick without any other options" or they are "looking to make money." In that same survey, 34% of Americans said that they "do not admire" people who volunteer for clinical trials. 

Poor public trust and confidence, along with low awareness, has diminished appreciation for the gift that participation plays in helping to advance medical knowledge and improve public health. 

There is wide agreement that numerous factors have contributed to the erosion of public trust and confidence in clinical research. 

During the past 10 years, the media has well publicized tragic study volunteer reactions to investigational treatments that have resulted in serious harm and death. Research sponsors and investigators have been charged and found guilty of data falsification and failure to disclose important safety information. Drugs have been withdrawn from the market due to poor safety profiles. Physicians have been indicted for failure to disclose conflicts-of-interest. Research sponsors, contract research organizations, and investigative sites have been accused and found guilty of clinical trial mismanagement and failure to protect volunteer safety. 

In addition, human subject protection programs have been charged and suspended for failing to provide adequate oversight. Pharmaceutical and biotechnology companies have been publicly challenged for submitting fraudulent safety data and manipulating study results in new drug and biologics applications. And the FDA has been charged with lax oversight, operating under capacity, entering into "cozy" relationships with industry, and accepting incomplete and fraudulent safety and efficacy data. 

The point is, no stakeholder group has been free from indictment. And, to date, no stakeholder group has responded adequately. 

At the same time that clinical research is being depicted in the media in such a negative light, the public has received little to no educational information to counterbalance public concerns and perceived risks. The public generally hears from the clinical research enterprise on two occasions: when a clinical trial is actively enrolling study volunteers, and when a new medical intervention has performed well and is about to be launched. But historically, the public has rarely received general information about clinical research and the mechanisms in place to oversee its performance, quality, and safety. 

Although the public is the most trusting of information from health care providers, medical and health professionals are largely absent from educating the public and prospective volunteer communities about clinical research. Only one out of seven Americans are exposed to information about clinical studies from their primary or specialty care physician and only one out of eight Europeans learn about clinical trials from their physicians. 

Regulatory agencies and the clinical research community have responded to public confusion and distrust by implementing reforms designed to assure higher levels of compliance and reduce errors that might result in physical and ethical harm to clinical trial volunteers. 

Since 2001, a growing number of universities have established clinical research degree programs. European and American regulatory agencies have implemented new privacy and conflict-of-interest disclosure guidelines along with new clinical trial registration requirements. Several trade associations have developed investigator certification programs. The National Institutes of Health (NIH) and private sector research sponsors have launched Web-based registries of clinical trial listings and results. 

These reforms and measures are an important step in ensuring the credibility of clinical research professionals. But they have not been well communicated to the public.  

Outreach and education are also critically needed to engage the public as partners in, and beneficiaries of, clinical research. These initiatives must be comprehensive in scope. CISCRP, an independent nonprofit organization, has been at the forefront of developing and implementing public education and outreach initiatives during the past several years. The impact of these initiatives is only beginning to improve public awareness, understanding, and trust. These initiatives are described in detail on the organization's Web site at 

Despite low levels of trust and confidence today, there is no evidence to suggest that the public will abandon the clinical research enterprise outright. This foundation of general support exists to rebuild confidence and trust through both training and education of clinical research professionals and through public education and outreach. 

The clinical research community has no time to lose in consistently supporting efforts—with resources and funding—that strike at the heart of public distrust.  

 MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: 

Clinical Trial Insights

The public considers clinical research important, but they're not fans of the people behind it.

Getting to the Heart of Public Distrust

 (King of Prussia, PA) is offering a new data-driven approach to site selection for clinical trials. With nine years experience under its belt with its physician masterfile and claims data, Health Market Science has integrated both datasets along with clinical trials detail into a data-driven workflow tool. The Web-based solution gives clinical trials professionals access to quantitative and qualitative insight into existing and potential trial sites. 

The product is called Clinical Investigators. Matt Plack, Marketing Director at Health Market Science, said, "Our market research found that most trial site selection relied on fragmented and outdated data limited to current sites, rather than the full universe of potential sites. Past site performance is only one indicator, so we focused on delivering real insight into which sites had the right location, affiliations with institutions, and potential subjects based on claims volume." 

In addition, Plack stated that they found many of the databases in use today by CROs or sponsors are not updated or managed on a regular basis, resulting in old and incorrect information about the sites. Also, these databases may not accurately reflect the investigator's current patient pool or current workload. 

By hosting the workflow tool, Health Market Science is able to refresh the physician masterfile data weekly, thus ensuring that research teams have highly accurate site contact information. This can reduce time wasted in contacting nonviable investigators. 

To access Clinical Investigators, trial sponsors and CROs license individual or multiple markets, which allows them to search for investigators with measurable experience in a specific therapeutic area. End users receive a user ID and password that allows them to research, save, and export detailed listings of potential investigators that can be used by other team members in the company. 

The industry factors behind the investment in and development of the Clinical Investigators solution are well-known to industry veterans: the day-to-day administrative costs for delays in a trial, combined with the overall costs to a biopharm company for delaying a drug to its NDA. Trial delays come in a variety of forms, and here we speak of subject recruitment delays. 

Related to subject recruitment are trends in the actual principal investigator world. Without physician investigators, there is no access to the needed patient turned subject. A notable trend uncovered by the Tufts Center for Drug Development is the high turnover rate among clinical investigators. Specifically, the basic fleeing of veteran investigators from the conduct of clinical research at a rate of 36% per year. The reasons? Tufts noted that profits for investigative sites are being eroded by increasingly complex protocol designs, subject eligibility issues, and cash flow problems at the site—all are cause for an investigator to leave the industry.  

Clinical Investigators addresses this trend by allowing site recruitment teams to expand the pool of new potential sites when known sites decline participation. According to Plack, "With the pool of known investigators static or shrinking, we're able to offer insight into other sites that may be worth considering. It gives them a wider view." As an example, Plack offered, "After filtering and sorting their results, they may find that a physician without experience is affiliated with a hospital that does conduct clinical trials, or that an experienced investigator is affiliated with that hospital." 

Plack and Zach Henderson, VP, marketing and product development for Health Market Science, acknowledged that physician information can be accessed and utilized from a variety of shapes, forms, and sources, including Google, silos of data within a company, internal and external databases, and more. "But this is a more scientific approach," explained Plack. "By integrating our accurate and timely masterfile data with known claims experience and trial detail, we provide a solution for a more centralized and efficient process." 

The data utilized in Clinical Investigators is for U.S.-based site selection. It contains data for over 650,000 physicians and over 6500 hospitals. 

Global trials and overseas site selection are yet additional factors in subject recruitment and clinical trials conduct in general. "The shift to overseas is a function of many things," Plack told 

. "These include greater selectivity of U.S.-based PIs and access to larger patient populations. The level of detail we provide about U.S.-based sites is not widely available for international trials, other than within the sponsors. It's very limited." 

Clinical Investigators was formally launched earlier this year on July 14. Henderson said that clients have been using the tool prior to launch, and were instrumental in the designing and refining of the final product. 

Health Market Science (King of Prussia, PA) is offering a new data-driven approach to site selection for clinical trials. With nine years experience under its belt with its physician masterfile and claims data

Next Generation Site Selection?

Over the past 10 years, the life sciences industry has faced the twin forces of fierce competition and ever increasing regulatory pressures. To get products to market faster and foster deeper innovation, a higher level of collaboration needs to occur between a company's traditional silos of information, and this collaboration needs to include outside partners and their extended business ecosystems. 

At the same time, pharmaceutical firms must be acutely aware of industry regulations and standards set by agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). The management of information is essential to reduce compliance risks and improve submissions to these regulatory agencies. 

With the advent of more robust discovery tools such as high throughput screening, the increased volume of information available from the human genome project, and the amount of unstructured content in the form of complex documents existing in multiple revisions within the enterprise, there is an explosion of information. This, coupled with the desire for companies to differentiate themselves through the creation and protection of intellectual property, leads to many firms becoming bogged down when it comes to managing content. 

Through our many conversations with multiple customers across the industry, it has become clear that there are multiple versions of the corporate truth with respect to discovery, development, sales and marketing, and manufacturing. There are multiple data vendors, with varying data formats, all of which must be utilized in the enterprise management of content. This has shown that data inconsistencies, as well as a lack of discoverability, categorization, and dependability, have become the norm rather than the exception. 

In such an environment, the need for pharmaceutical and biotechnology companies to better manage their documents and content is greater than ever. This has opened the door for next generation enterprise content management (ECM) solutions—solutions that better adapt to how researchers, marketers, clinicians, and other employees work, while seamlessly adhering to regulatory requirements. 

Poorly managed data is most problematic when submitting content to regulatory agencies like the FDA. According to several of our customers, there are multiple documents that make up the entire electronic common technical document (eCTD) submission. These documents are linked to one another in that they refer to one another and are therefore linked. This link is maintained as part of the submission. A typical FDA submission can contain more than 100,000 links. Companies have to manually check the links before finalizing submissions and turning them over to the government. Moreover, they have to find a way to relate unstructured content stored in file systems, users' computers, and content management systems to other content located throughout the organization. 

A typical submission requires input from many people that spans departments, organizations, and years. All of the documents in a New Drug Application (NDA) submission, for example, need to be reviewed by various people in the organization before they are included in the submission. The movement of these documents around the organization and the sign off and approval that must happen during that movement constitute a workflow. Today, submission workflow is an incredibly inefficient process. It consists mainly of authoring a document in Microsoft Office Word, rendering the document to PDF, and then setting links using a multitude of Adobe Acrobat plug-ins. If the relative path of the target document changes after the links are set, the links break. 

The ultimate goal, of course, is to meet the requirements of an eCTD submission, which can be found at http://

estri.ich.org/eCTD/eCTD_Specification_v3_2.pdf

. An unstructured content authoring environment, however, makes it difficult to create intelligent documents without major customization. 

What's needed is a central and trusted repository for all content that is subject to regulation. A central and trusted repository is secure and validated. It is available across the organization to those individuals who need to have the information. It can be audited at any time and the movement of documents in and out of this repository can be tracked and detailed. The content should be moved to and managed in this repository based on metadata and lifecycle rules. For example, what is the status of a particular piece of content? Which is the original and which are the copies? Where is the latest approved version of a document? A large portion of corporate content is redundant, and there is no way to know which document is the authoritative original. 

Life science organizations must realize that the ECM lifecycle is extensive, with the ability to move information from creation and capture to management, to sharing and collaboration, to publication, and to archival or disposal. These considerations have forced organizations to review the challenges of content management within their enterprises and move beyond traditional filing and document repository systems. 

The digital age has brought with it a wealth of content in a multitude of formats, such as images, text documents, Web pages, spreadsheets, presentations, graphics, drawings, email, instant messages, video, and multimedia. The magnitude of structured and unstructured content can be complex and difficult for organizations to manage. 

Life science organizations have considered many strategies on how to structure and manage the content they generate and consume, both from a recordkeeping and a document management standpoint. In the context of an overall ECM strategy, organizations need to address explicit requirements within three major areas: document management, records management, and forms management. 

In records management, for instance, some of the particular requirements include establishing retention and expiration policies and minimizing outdated information within the organization. These specific requirements and others could all be addressed with an ECM solution, by maintaining a controlled environment wherein access is based on roles and is time-bound—one can control who sees the information and in what time frame that information is available. Once a document reaches its expiration, it can be moved (through business rules that are part of the system) to a repository that can only be accessed through auditing and not be accessed for reference as a live document. That way it is retained but not used. With an ECM solution, one can "time-bomb" documents so that they cannot be referenced or used passed a certain date. 

The requirements of 21 CFR Part 11 on industries regulated by the FDA has been wide-ranging. The rule affects electronic records stored in databases as well as electronic records created by word processors, spreadsheets, and graphics programs. The capabilities of conventional productivity applications need to be supported by a solution that can control the integrity and security of electronic records authored in those tools. 

Regulatory requirements and legislation, such as the Sarbanes-Oxley Act, have changed ECM from an optional nice-to-have capability, to a must-have system. Enforceable document retention policies, consistent records management, and systems for managing unstructured information are all requirements from the standpoint of compliance legislation and regulations. 

Although legislative requirements are a major factor, there are other reasons to consider an ECM solution. Organizations need to exert control over a massive volume of records and documents as a way to reduce task duplication and minimize the time employees waste looking for out-of-date documents or, worse, recreating documents. 

In addition, managing content helps ensure that the right information in the right format reaches the right decision makers. After decisions are made, content management practices help preserve the why, when, and how of those decisions. 

True efficiency requires the move to a company-wide ECM solution that supports the entire content lifecycle.

Applied Clinical Trials-09-01-2008

At Home Testing Offers Solution

Simulated Strategies for Better Trials

Global Trials Draw Regulatory Scrutiny

The Ins and Outs of Electronic Medical Records

Getting to the Heart of Public Distrust

Next Generation Site Selection?

Breaking Barriers to Enterprise Content Management

From Paper to Electronic the FDA Way

Foreign CROs Break Into U.S. Market

EU Scorecard on Medicines for Children

Business and People Update September 2008

Taking Your John Hancock Digital

A Revised Approach to Early Trials