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SUBJECT RECRUITMENT : Integrated Team - Sponsors, CROs, and Sites  Patient Tracking Services Can Help Reduce Lost to Follow-Up  TRIAL DESIGN : Pediatric Trials - Errors in Informed Consent  Also in this issue : Common Rule Revision, EU?s Health Policy and Clinical Trials, CROs Going Private, Research Clusters

Applied Clinical Trials Digital Edition - September 2011

A recent study conducted by the Tufts Center for the Study of Drug Development (Tufts CSDD) found that more than half of all protocols require one or more amendments. Based on data from 3,410 protocols provided by 17 large and midsize pharmaceutical and biotechnology companies, Tufts CSDD found that completed protocols across all phases had an average of 2.5 amendments requiring 6.9 changes to the protocol per amendment. Later-stage Phase II and III protocols had a higher average number of amendments, 2.7 and 3.5 respectively. The most commonly cited causes of amendments included the availability of new safety information, requests from regulatory agencies to amend the study, and changes in the study strategy. Protocol design flaws and difficulties recruiting study volunteers were also cited as top causes. The study found that the incidence of amendments is associated with protocol complexity and duration. The mean number of amendments per protocol, for example, was positively and significantly correlated (p<.001) with the number of procedures per protocol, study length, and the number of investigative sites conducting that protocol. 

—Tufts Center for the Study of Drug Development, 

 Mean number of amendments per protocol. (Source: Tufts Center for the Study of Drug Development) 

A recent study conducted by the Tufts Center for the Study of Drug Development (Tufts CSDD) found that more than half of all protocols require one or more amendments.

Most Protocols Require Multiple Amendments

Patient recruitment plays a major role in establishing the objectives and the ultimate success of clinical trials. Yet, targeting the right patients and retaining their participation is one of the greatest challenges currently facing the biopharmaceutical industry.  

Traditional recruitment methods have proven inadequate, with the majority of trials failing to enroll a sufficient number of patients in a timely fashion. As the biopharmaceutical industry continues to face challenges such as increasing costs, reduced productivity, and shrinking pipelines, it can ill afford costly delays associated with recruiting and retaining patients for clinical research.  

Historically, the responsibility for patient recruitment primarily belonged to investigator sites. Today, sponsors and contract research organizations (CROs) are partnering with sites and a broad range of stakeholders, including operations, site monitors, site staff, and recruitment specialists, to drive enrollment. Sophisticated planning and coordination among all parties is necessary in order to successfully carry out effective and efficient patient recruitment. 

In this article, the opportunities available to improve patient recruitment strategies by taking an integrated team approach supported by effective communications, process improvements, and a deep understanding of each stakeholder's role are examined. Topics discussed include:  

Challenges to patient recruitment currently facing the biopharmaceutical industry 

The role of the sponsor and CRO in recruiting and retaining patients

The role of investigator sites in recruiting and retaining patients

Communication strategies that best support trial sites in patient recruitment efforts

The importance of each member of the trial team carrying out his or her role for the benefit of the entire trial.

Patient recruitment is critically important to the health of biopharmaceutical research activities, and an area of growing concern. Today nearly 80% of clinical trials fail to meet enrollment timelines

  and up to 50% of research sites enroll one or no patients.

A lack of study participants poses a major threat to the industry by causing delays in new drugs making their way to market. This translates into as much as $8 million in lost revenue for each day a drug is delayed.

  In addition, failure to enroll the necessary number of patients at each investigator site in a timely manner can compromise a trial's statistical power and scientific validity.

Challenges to patient recruitment have been exacerbated in recent years by a number of factors. For one, there has been a dramatic expansion in the number of trials being conducted, which has heightened competition for patients. At the same time we've seen an increase in trials, the number of new investigators has not increased significantly. Between 2000 and 2007, the volume of studies has increased by approximately 15%, and the number of new investigators has declined by 10%.

Increasing study complexity and eligibility criteria is another contributing factor to lower patient enrollment and retention rates. Over the past decade, the average eligibility criteria for clinical trials have increased by 58%, while volunteer patient enrollment rates dropped by 21% and retention rates fell by 30%.

With a more competitive landscape, advances in recruitment practices must be implemented if the biopharmaceutical industry is to meet the growing demand for patient participants. In large part, that will require a thorough re-evaluation of the roles and responsibilities of trial professionals; each member must focus on mastering his or her particular area of specialty in the service of the larger goal of the trial.  

Figure 1. Growth in the number of new studies is met with declining growth in the number of investigators. 

The sponsor, and by extension the CRO, plays a key role in facilitating a clinical trial site's patient recruitment activities. 

 A clear channel of communication between sponsors/CROs and trial sites is essential to successful patient recruiting efforts. In order to establish a more collaborative and, therefore, more informed approach, sponsors/CROs should consider strategy meetings and direct discussions with sites early on to learn about key obstacles and suggestions for operational efficiencies. These meetings should be used to define the elements of the protocol that will create challenges for patients and/or site personnel. This information can be used to make appropriate protocol modifications and to define the key areas to address when communicating with patients. It's important that investigator sites are given the information necessary to evaluate all aspects of a study's feasibility. Sponsors/CROs that are candid up front about potential challenges and provide adequate time and information to trial sites will benefit in the end from the more accurate information gleaned from this process.  

Overly complex or unrealistic protocols are one cause of trial delays and have a negative and costly impact on the ability to enroll and retain patients. The feasibility of a trial, therefore, must be carefully examined to ensure that assumptions made early on are supported by a comprehensive set of data collected from multiple sources. 

 Allowing investigator sites to conduct a thorough review of patient charts as part of the planning process is an important step in identifying and enrolling appropriate trial participants.  

The process of carefully reviewing patient charts and evaluating them against protocol criteria requires a significant commitment of time on the part of investigator site staff. If the job is to be prioritized, the sponsor/CRO should consider compensating staff for this important task. Providing financial support for the time it takes sites to mine their medical charts for potential trial volunteers makes it possible for sites to invest the resources necessary to thoroughly carry out chart reviews and focus on rapidly recruiting the most appropriate patients.  

 Leveraging electronic health data is a critical tool for establishing more sophisticated patient recruitment strategies throughout the industry and will play an increasingly significant role in helping to coordinate the efforts of trial teams as they are adapted across the medical profession. 

For practices currently using electronic medical records (EMR), sponsors/CROs have an opportunity to capitalize on this technology by providing resources to help the site work through their EMR system to conduct feasibility assessments and identify appropriate patients. Some EMR vendors, for example, have the capability to write a trial protocol query that an investigator site can run against their patient database to identify potential trial participants. This can be a very effective way of identifying patients who might be appropriate for the trial, and is a tool that the sponsor should consider.  

 Approximately 69% of non-participation in clinical trials is the result of a lack of awareness that a trial is even taking place.

  That underscores how critically important effective communication is to the success of patient recruitment, and ultimately, to the trial itself.  

There are a number of ways to most effectively get the message out about a trial. First, the sponsor/CRO should provide each investigator site with patient communication materials. Brochures, posters, placards, and pocket tri-folds can accomplish two important objectives:   

Keep the study top-of-mind for trial site staff so they remember to offer the study as an option for the patient

Help facilitate communication between staff and patients 

When written without medical jargon and in terms that patients can easily understand, communication materials at the trial site play an important role in helping patients become more informed about what it means to be a trial volunteer. 

Quintiles has tracked and evaluated the impact of distributing site materials and found that well designed communication tools drove a 20% to 60% increase in consented patients willing to be screened. It was found that there is a greater benefit to distributing these materials early in the trial.  

Supporting sites in the effort to identify and recruit patients from outside of a practice also relies heavily on well-crafted patient communications and is an area in which sponsors/CROs should take an active role.  

Today, it's more important than in previous years to help sites reach beyond their practices to find patients. Increased competition for patients and recognition that advertising is not typically an area of expertise at the site level requires communication professionals to join the team and establish the most effective channels by which to reach the patient population of interest.  

As a starting point, marketing research is necessary in order to uncover the key issues and questions patients have about participating in a trial. This plays a critical role in the development of appropriate messaging aimed at encouraging and enabling patients to seek more information about participating in a clinical trial. 

Sponsors/CROs can then make it easy for sites to advertise by supporting them with media buying expertise to ensure that the most effective form of media to attract the target patient market is being deployed. To facilitate media buying, some CROs and sponsors provide sites with an advertising tool that allows investigators to select media online and then access the expertise of professional media planners and buyers to negotiate its purchase. Additionally, tracking the results of the campaign can be used to drive process improvement on an on-going basis. In some cases, an advertising account is established so that trial sites simply draw on a fund rather than submit invoices for each media buy. 

Finally, sponsors/CROs can make available to sites opt-in databases of patients interested in participating in trials and help the sites pre-screen those patients ensuring only the most qualified applicants are referred. Pre-screening can be done by a call center or online questionnaire that captures self-reported patient information. While it's not possible with this method to address all inclusion and exclusion criteria, basic parameters such as patient age and medications can be covered to improve the likelihood that the patients referred are strong candidates for the study. 

Naturally, the investigator sites must also play an active role in recruiting patients for the trial they will conduct.  

Physician investigators, specifically, play a critical role in helping sponsors/CROs understand how patients interact with the healthcare system and how they will move through a particular study. This kind of "on-the-ground information" is essential to sponsor/CRO efforts to establish protocols that are less complicated and maximize convenience for both patients and site coordinators.  

Investigators and clinical coordinators should also be involved in reviewing a draft of the study design and provide feedback early on so important adjustments to protocols can be made. It is important to ensure that assumptions are based on data rather than anecdotal experiences.  

Contributions to communication/education. 

By talking openly with patients early on about participating in a clinical trial, sites can solicit feedback to help in the development of educational materials that specifically address patients' most pressing questions and concerns. It also provides an opportunity for site staff to educate patients about the specific benefits of participating in a clinical trial. For example, that their own health will be closely monitored, or that it's an opportunity to contribute to a body of scientific knowledge that may ultimately help treat other individuals who share their illness. 

It's important for sites to recognize and leverage the tools and expertise provided by sponsors/CROs. Often, investigators go it alone when it comes to recruiting patients, attempting to market and advertise the study themselves. Expertise regarding how best to implement some of the necessary activities for successful patient recruitment is available through sponsors/CROs and should be utilized. The most effective sites work collaboratively with experts and adapt patient recruitment methods to fit their environment. They do not attempt to master them on their own.  

Following up with patients who come to the study through media or opt-in databases is another critically important aspect of successful patient recruiting for investigator sites. A failure to contact patients in a timely manner reduces participation greatly—one study found that sites that waited to follow-up with patients experienced a 68 percent decrease in participation as compared with sites that followed up within one day of referral.

Once recruited for a study, it is important for the investigator site to establish and maintain a relationship with the patient and to manage that relationship proactively. Study volunteers, after all, are giving up a lot of personal time and may be making a significant sacrifice. It's important that investigators keep this fact in mind and treat trial volunteers with a customer service orientation. 

Feature Article

Sponsors, CROs, and investigator sites must all work together for effective patient recruitment.

Recruitment Roles

Research experts, patient advocates, and government officials have examined options for improving oversight of human subject research for years, often in response to periodic scandals involving patient abuse and unethical conduct that heighten public interest in the clinical research process. Now federal officials have put a major reform proposal on the table, with an eye to enhancing protections for research subjects while also reducing burdens, delays, and ambiguity for investigators. The change involves a lengthy and detailed proposal for revising the Common Rule, which was published in July by the Department of Health and Human Services (HHS), in coordination with the White House Office of Science and Technology Policy  (Federal Register, 76 (143), 44,512-44,524 (2011). HHS is receiving comments to the Advanced Notice of Proposed Rulemaking until October 26, and the breadth and depth of the proposal is sure to generate a considerable response. 

The Common Rule generally requires investigators and sponsors to obtain and document informed consent by research participants and to undergo review by institutional review boards (IRBs), spelling out a host of requirements for investigators and review board operations in the process. It was developed and revised through the 1970s and 1980s and adopted in 1990 by 14 federal agencies as the Common Rule for the protection of human research subjects. 

The long and convoluted process for establishing these standards, though, has led to a policy that can be overly burdensome and bureaucratic, often accused of driving up study costs and failing to protect research participants. Although the Common Rule directly affects research funded by the US government, the contemplated changes stand to shape policies for industry-sponsored studies regulated by the Food and Drug Administration. Proposals to streamline informed consent, adverse event reporting, and IRB oversight could make the research process more efficient, while new standards governing data privacy and disclosure could require new approaches to clinical trial conduct.  

The reform proposal is timely, according to HHS, because the scope and nature of clinical research has changed notably since the last revision of the Common Rule 20 years ago. Research has shifted from academic medical centers to hospitals and doctors' offices, while sophisticated software and mobile technology have altered the landscape for protecting the privacy of research data. Investigators and sponsors, moreover, are conducting more clinical studies overseas, which only adds to the confusion over which standards to follow.  

An added impetus for proposing this broad regulatory reform initiative is the campaign launched in January by President Obama to identify, eliminate, or modify those federal regulations found to be excessive. Revising the Common Rule fits that mandate, even though it could mean added regulation in some situations.  

HHS officials were able to move quickly to publish this extensive reform proposal because of a long history in examining human subject research practices and policies. Over the last few decades, the Institute of Medicine, the Government Accountability Office, and the National Bioethics Advisory Commission have offered multiple reports with a range of recommendations for revising oversight and review of research. 

In addition, the HHS Office for Human Research Protections (OHRP), which was formed in 2000 to address concerns about inadequate oversight of clinical research by the National Institutes of Health (NIH) and other HHS agencies, has evaluated and proposed multiple policy changes governing oversight of federally funded research. The Secretary's Advisory Committee on Human Research Protections (SACHRP), which OHRP manages, has examined ways to harmonize and clarify rules governing informed consent, conflicts of interest, safety assessment, and IRB operations, among many other issues. SACHRP subcommittees continue to explore problems related to federal policies and to harmonize diverse federal standards, particularly differences between HHS and FDA policies. 

Moreover, the Presidential Commission for the Study of Bioethical Issues is reviewing how well US research regulations protect human research subjects in response to a formal request from President Obama. Concerns about US policies emerged last year following revelations that a US-funded study in the 1940s in Guatemala deliberately infected people with sexually transmitted diseases and in some cases withheld treatment [see 

]. In addition to assessing the Guatemala study specifically, the panel is examining the scope and sufficiency of controls and regulations governing US-funded research. In the process, the commission seeks to assemble a database on federally supported scientific studies, including how many people are enrolled and how much money the government expends in this field.  

At its May 2011 meeting, Christine Grady, Deputy Chief of the Department of Bioethics at the NIH Clinical Center, described how the common rule differs from FDA good clinical practices regs (GCPs) and how the proliferation of federal guidelines can be overwhelming and frustrating to investigators. The sheer number of rules and guidances can discourage scientists from conducting clinical research at all, she acknowledged, and burdensome rules can delay approval of new studies for years, with potential harm to patients.  

Murray Lumpkin, FDA Deputy Commissioner for International Programs, outlined how the growth in foreign clinical trial data submitted to support US marketing applications has expanded the agency's role in ensuring that data from foreign clinical trials is obtained in an ethical manner. With half of clinical investigators involved in FDA-regulated studies now based outside North America, he noted, the agency finds it increasingly challenging to inspect clinical sites to ensure that studies meet GCPs and have appropriate oversight by independent ethics boards. Lumpkin agreed with Grady that GCP guidelines developed by the International Conference on Harmonization (ICH) have become an international standard, but that US researchers have to understand local differences in key issues such as standard of care and legitimate consent.  

In this latest effort to update the Common Rule, HHS officials seek to take a more risk-based approach to research oversight, permitting expedited IRB review and less continuing review for studies categorized as "minimal risk." At the same time, HHS proposes to extend Common Rule oversight to a much broader scope of research. Instead of applying only to those studies that receive government funding, research standards would cover all research at institutions that receive any federal funds. The aim is to bring more social science and behavioral research under the Common Rule umbrella, but the change could affect industry sponsored research with sites at hospitals, clinics, or academic research centers.  

An important change for sponsors of multi-site studies is new flexibility to designate a central IRB of record, a move that would reduce IRB workloads and permit them to focus on more critical oversight activities, while also simplifying compliance for investigators. Oversight also would be enhanced by an electronic system for reporting adverse events that would feed all safety information from federally-regulated studies into a comprehensive database. This would utilize a harmonized data set for adverse event reporting developed by FDA, NIH, and other agencies and now being tested by NIH and FDA in a harmonized reporting system for gene-transfer studies.  

Similarly, the reformers seek to improve informed-consent requirements and the consent process. The proposal cites ways to reduce the length and legalese in these documents to help subjects make informed decisions about study participation. An important issue is the need for consent for future use of biospecimens and research information. Current rules permit investigators to use blood and tissue samples in subsequent research without added consent because such material is not individually identified; now HHS proposes that researchers obtain explicit permission from tissue donors for future use of such material because new DNA sequencing technology makes it possible to link tissues to specific donors. 

HHS justifies looser controls and less oversight of certain research activities on its plan to extend privacy protections to research data. The proposed rule seeks to establish uniform security standards for research data modeled on the protections provided by the Health Insurance Portability and Accountability Act for medical records. Related to this, IRBs no longer would have to evaluate privacy and confidentiality standards for research studies, a fairly recently added responsibility that has been difficult for most review boards to carry out.  

For the most part, industry sponsors and investigators adhere to FDA standards that are more specific than those for academic researchers. OHRP has been working with FDA on harmonization efforts for more than a decade, but legal requirements limit how much FDA can modify its policies. Officials at these agencies are keeping pretty mum about the implications of the rule changes until they see what kind of response they get from the research community and patient advocates. Changes of this magnitude will take years, but some could make clinical research more efficient and effective.  

At the May bioethical commission meeting, Wellesley College Professor Susan Reverby, who uncovered the controversial Guatemala study, raised concern that the resulting discussion about unethical research practices could make people afraid to participate in clinical studies, which make "a huge difference in the lives of every person on this planet." 

View from Washington

Modernizing the Common Rule to update research policies could spell important changes.

Uniformity Sought for Research Standards

The European Medicines Agency has confirmed its long-term commitment to remain in London by signing a 25-year lease agreement for office space in a new 20-story building on the Canary Wharf estate. The Agency plans to move in 2014, when the leases on its current premises expire. 

The EMA will lease the basement, promenade, ground, and first nine office floors. It has agreed a pre-let of 250,000 square feet (23,226 square meters) in a new office building of over 500,000 square feet to be constructed at 25 Churchill Place, close to the Agency's existing properties at 1, 7, and 11 Westferry Circus, also at Canary Wharf in London, where it currently occupies around 225,000 square feet. 

 A computer-generated image of the EMA’s new home, located in the Canary Wharf Estate.			

The agreed rent is £46.50 per square foot (about $75.35) commencing on January 1, 2015, with five yearly upwards-only rent reviews. The EMA has options to take an additional four floors of around 27,500 square feet each. It will receive a 37-month rent-free period, which will be used to pay for decorating and equipping the building. 

"The new building will enable the agency to improve the efficiency of its use of space, reducing its annual expenditure. The agency hopes to cover the costs of relocation with the savings that these reductions will bring over the first 10 years of its tenancy," noted a press release issued by the EMA on August 9. "The Agency will not need to pay any costs towards construction." 

Work on the tower is due to begin in the fourth quarter of 2011. Energy-efficient, environmental features will include elevators that store and reuse energy elsewhere in the building, and air-conditioning equipment that recycles the energy from exhaust air and photovoltaic cells to generate energy from the sun's rays. The building will have a "green" roof, which enhances biodiversity and energy efficiency. 

As many as 1,000 direct jobs, plus several thousand indirect jobs, will be supported in the construction and supply of materials and components, giving a further boost to the local economy, according to the landlord. 

"We are very pleased to provide the EMA with a building that responds to their new requirements, offering new technology and significant organizational and environmental efficiencies," said George Iacobescu, Chairman and Chief Executive of Canary Wharf Group . 

The new tower will be one of the most energy-efficient office buildings on the Canary Wharf Estate, and it will achieve an "excellent" environmental performance rating and an Energy Performance Certificate rating of 40 or better, he noted. The balance of the space will be marketed by Canary Wharf Group as construction progresses. As a result of the pre-let to EMA, the landlord is in advanced discussions about funding for the project with a number of lenders.  

Construction of the shell and core and decorating will be undertaken by Canary Wharf Group. The architects will be Kohn Pedersen Fox Associates. News International had originally intended to occupy the site, but the media group pulled out, leaving the site undeveloped. 

The President of the European Parliament, Jerzy Buzek, informed the EMA of his agreement over the relocation on July 18, 2011, following a favorable opinion from the Committee on Budgets. 

About 95,000 people work at Canary Wharf, and the number is projected to double by 2025. Around 20% of the estate consists of landscaped parks, plazas, and walkways with over 1,000 trees and 88 floral species. Each year 70,000 seasonal plants are planted. 

There are more than 200 shops, bars, and restaurants on the development. Recent openings include Levi Strauss and Charles Tyrwhitt. Seven new bars and restaurants have opened there during the past 18 months, creating over 400 jobs. Current projects underway outside Canary Wharf include the 20 Fenchurch Street "Walkie Talkie" which is a joint venture with Land Securities, and the redevelopment of the Shell Center on the South Bank, a joint venture with Qatari Diar. 

During the construction of the EMA's new office, much of the equipment and materials will be transported by water, minimizing carbon emissions and congestion on local roads. 

Global News

The EMA is moving its offices to Canary Wharf Estate.

EMA Commits to London for a Quarter Century

When choosing a technology for a patient-facing clinical trial, the selection of the most appropriate data collection tool for the population using the study drug is a major factor. In the Pfizer Phase IV study of Detrol LA for overactive bladder (OAB), this was the case, as most women with OAB are usually in their 60s. The eDiary device that was chosen was a Nokia cell phone, which were all pre-programmed and loaded with the eDiary application for each study subject's use. Additional costs of using a smart phone and the limits to the smart phone technology that could be unfamiliar to this therapeutic population were eliminated by using an ordinary cell phone. 

Exco InTouch specializes in interactive mobile solutions for many areas of clinical trials including recruitment, retention and compliance, postmarketing trials, and ePRO. Pfizer chose Exco InTouch based on previous experience using its technology in another trial. Its validated ePRO solutions include SMS or text technology; diary collection by mobile Internet cell phones; and application technology for smart phones, PDAs, tablets, and PCs. In the REMOTE trial, Pfizer used the cell phone with proprietary technology, programmed for local languages, timed messaging, and text reminders for subjects to record medications, volume of urine, and other protocol specific questions. The data are then transmitted real time to Mytrus servers, the virtual coordinating center for the trial (see 

Virtual is one of the key words for the REMOTE trial—other terms to describe it are clinical-trial-in-a-box, patient-facing, or patient-centered. What it means is that Exco, along with Mytrus, Greenphire, and Perceptive Informatics, are providing solutions in this new clinical trial model that Pfizer is evaluating for methodology only. Mytrus serves as the single coordinating center for patients, recruitment, the principal investigator, sub-investigator, and the coordinators; Perceptive Informatics is providing IVRS; Exco InTouch is providing the eDiary; and Greenphire is providing pre-paid debit cards for subject payments.  

In designing their part of the virtual program, Exco CEO Tim Davis said, "We had to think creatively. There would be no direct interaction with the patient meaning the site nurse wouldn't be there to train the patient on the device since the trial isn't site-based. We created an interactive training module on a DVD that came with the phone." Davis also said that they engineered the product and process so the patient could do as much as possible out of the box as well as to reduce the number of calls made to the call center that Mytrus was running. 

Exco used a pre-formatted, publicly available paper-based questionnaire that it adapted internally for ePRO use and translated to the mobile phone. Pfizer then validated the questionnaire and device in accordance with FDA Final Guidance for PRO (December 2009). 

Davis feels comfortable with the level of technology, support, validation of the ePRO questionnaire, and phone use. The company has conducted trials in this patient population, as well as trials in urology, and is very glad to be a part of the first trial of this kind. "We are obviously supportive of it [the trial]," said Davis. "In the current environment, we don't expect the ability to do all clinical trials this way. But with this kind of therapeutic area, it is a great way to do it." Davis believes for this therapeutic area, it is underserved and very hard to recruit patients because of the nature of the condition and the challenges associated with unobtrusively fitting in the collection of how to fit the patient information recording into their day-to-day life. "If we have done that, then that is a positive," said Davis. "For certain therapeutic areas, this is the way forward. It is the way the world is going."  

Davis acknowledges that virtual trials circumvent the site engagement activity, but this is necessary as a part of driving down the cost of trials. "People are looking at that incredibly seriously," noted Davis.  

will profile Greenphire's technology use in the REMOTE trials. 

News

Companies such as ExcoInTouch, Pfizer, and others are turning to mobile technology.

Cell Phone Key to REMOTE Data Collection

What is a cluster? A cluster is a way of organizing a group of competing companies in geographic proximity to one another. Perhaps the most well known clusters in the drug development world are the biotechnology clusters in Cambridge, Massachusetts and San Diego, California. There are further clusters in Scandinavia and throughout Europe, and new clusters are appearing in the Asia Pacific region.  

The concept of clusters is not new. Researchers have studied clusters in detail and have settled into two schools of thought. The first group extols the benefits of operating in the cluster model. They perceive the phenomenon of "spillover" to be highly beneficial. Spillover occurs where one firm in the cluster can leverage a resource available at one of its neighbors. Knowledge gained in one company can be accessed by others through local networking events (be they formal or social), or by hiring their new staff from them. A person operating in a similar company in the same geography will bring useful procedural knowledge to the hiring firm. In contrast, the second group believes that the number of relationships a company has is more important than proximity of links. They cite an increasingly sophisticated telecommunications infrastructure and the shrinking of the world as nullifying the competitive edge gained by companies choosing to operate in a cluster.  

While clusters provide many benefits to those companies that choose to operate within them, my view is that those same benefits of an ordered system can also harm innovation. I question whether operating in a cluster is the right decision for a drug development company, or indeed any knowledge-based organization. Access to suppliers, the power of group buying syndicates, the ability to hire qualified staff without relocating them, and the political strength in numbers are all useful attributes for those in the cluster. But, at what cost? 

Once a firm joins a cluster and begins to leverage knowledge spillover, the environment restores an element of order to the system. There is a growing body of evidence in academic literature that suggests that, for innovation to thrive, a more chaotic environment is better. For example, a head of discovery moving from one company to another and imposing similar standard operating procedures at the new company. Prior to the move, two groups might have tackled a problem in different ways, now they may try to tackle it in the same way. Staff exacerbate the problem as they move to their third or fourth companies. Of course, this situation could just as easily occur when a person moves from one country to another, the difference in the cluster is that other factors increase the risk. For example, where a head of discovery moves within a cluster, the risk that their members move too is higher compared to the same person undergoing an interstate or inter country move. Furthermore, local networking events and presentations could lead to certain approaches being implemented across the cluster and becoming the "norm."  

An ordered approach has many benefits, but can also have downsides. Group purchasing schemes increase purchasing power but limit the number of vendors in the value chain. Membership of local trade groups aligns the political views of those members but can stifle change just as easily as promote it. Joint presentations at funding events brings access to money but introduces the members to the same potential funders. While order might be useful for smaller firms to do business, it is not useful in helping them to innovate.   

Clusters have a place in the commercial world; I am just not sure they have a place in drug discovery. 

 Commercial Director and  President of US Operations  Quanticate  

A Closing Thought

While order might be useful for smaller firms to do business, it is not useful in helping them to innovate.

Clusters' Last Stand?

New analysis has shown that proactively adopting patient tracking solutions can dramatically lower lost to follow-up (LTFU) rates and increase the efficiency of existing retention activities, but the systematic adoption of these services to support long-term trials is not yet widespread. With many clinical trials conducted today requiring long-term patient follow-up, it is important for sponsors to have access to cost-effective solutions to increase patient retention and reduce LTFU rates. 

Patient tracking services are independent, centralized registries of clinical trial subjects that actively maintain and update patient contact details, and allow sponsors to rapidly communicate with study subjects while protecting each subject's anonymity. Tracking services have a relationship with each clinical trial subject that is independent of any relationship with a trial, site, or sponsor—usually obtaining consent for regular, enduring communication even in the event that a patient has completed the study or withdrawn consent for study participation.  

In contrast to sites that have limited resources to apply to patient tracking, patient tracking services apply centralized, dedicated resources, processes, and systems to ensure that patients remain highly contactable. This involves the systematic collection and verification of detailed patient contact information at the time of patient registration. It also involves systematic, regular patient outreach that frequently involves multiple phone calls, often after hours. Patient tracking services also have access to a variety of third party databases to locate patients that may have moved suddenly or died. The centralized nature of patient tracking services allows sponsors to recontact patients rapidly across all sites in all regions—avoiding problems associated with variability in site responsiveness. Since patient tracking services establish a relationship with patients that exists independently of sites and obtain consent that is independent of the study they can easily recontact patients that have withdrawn consent from the study, or have separated from a site on unfavorable terms—a situation that can occur when patients experience significant side effects, or fail to meet their treatment expectations while participating in the trial. BINTO, a provider of international patient tracking services, routinely maintains active contact with patients during a study and up to five years after a study has completed. 

Recently, BINTO conducted a survey of project managers across the globe to quantify the challenges of LTFU in clinical trials. Not surprisingly, rates of LTFU tended to become significantly greater over time, ranging from 7.3% after 12 months up to 27% after 48 months. The most striking finding however, was that projects using proactive patient tracking solutions experienced dramatically reduced LTFU rates, at only 0.8% after 12 months rising to only 2.4% after 48 months. More information about the survey can be found in the Study Results sidebar.  

Study Results Highlight a Solution for LTFU in Long-Term Studies			

Failing to account for the welfare of patients during a study can affect the validity of its safety final results

—particularly when looking for relatively low numbers of safety events in comparison to the number of patients LTFU. For example, the conclusions drawn from a study of 1,000 patients that resulted in two deaths and 48 LTFU patients are limited regarding a mortality rate. As pharmaceutical companies strive to quantify rarer safety signals, even LTFU rates as low as 3% or 4% could invalidate the investment associated with a five-year safety trial. Over 92% of project managers surveyed indicated that they viewed proactive patient tracking as a valuable or very valuable tool for their studies, although less than 13% of long-term studies actually employed such a solution. 

A sponsor company running a global Phase IIIb study with a two-year follow-up, developed problems with LTFU within three months of start-up. Seeking to address this problem rapidly, the sponsor deployed a patient tracking solution resulting in LTFU less than 1% at the end of the study. More than 12 months after the study was completed, the sponsor was still tracking 6,247 of the 6,296 patients (99.2%) enrolled. The sponsor is now planning to use its continued access to these patients to rapidly enroll a new Phase III trial for a follow-on compound—potentially saving more than 18 months of recruitment time.  

Figure 1. Proactive patient tracking keeps LTFU to a minimum.			

Spurred by the fallout over Merck's Vioxx (rofecoxib), which was withdrawn from sale in 2004 after evidence emerged that raised concerns over the drug's cardiovascular safety, extensions to Phase III trials, or Phase IIIb/IV studies are increasingly required by regulatory authorities. Both US Food and Drug Administration

  have been increasing their demands on pharmaceutical sponsors for long term drug safety monitoring and risk management research. 

In addition to reducing LTFU during a study, patient tracking services continue to add value by maintaining contact with patients after study close-out and thereby reducing the need for costly study extensions. Sponsors that are able to recontact patients after a study is completed are able to address long-term safety concerns using data gathered from patients with randomized exposure to their drug.  Sponsors that are unable to recontact their patients must restart long-term safety studies from scratch, rather than revisit patients that were previously exposed to their investigational product in earlier years—adding significant cost to their post-marketing efforts and impairing their product's ability to obtain market access in the fastest way possible. 

In the same survey, project managers were asked how easily they could contact patients one year following the closure of a study—in response to a safety concern that appeared during final analysis or a regulatory request for example. Overall, project managers felt that less than 15% of patients could be recontacted without a tracking service, contrasting with the over 99% 12-month patient re-contact rates obtained when a tracking system was used. 

A second sponsor who contributed to the survey, had chosen to use a patient tracking service for an oncology study with 12-month follow-up. During subsequent regulatory review, the sponsor was asked to provide two-year survival data in addition to the original results obtained during their trial. The sponsor was able to recontact patients within a few weeks—accounting for 99.7% of their randomized patients two-years after initial treatment, and allowing the sponsor to address regulatory concerns rapidly without the cost and time associated with starting a new study or re-opening sites. 

In addition to reducing LTFU during a study, patient tracking services can increase the effectiveness of patient retention efforts. Traditionally, to maximize retention rates, many sponsors choose to have sites make phone calls to patients between visits and/or provide sites with patient retention materials to keep subjects engaged. In addition to allowing sponsors to reduce LTFU and facilitate long-term patient data capture, patient tracking services ensuring that retention materials, reminders, newsletters, and other interventions are reliably delivered to study subjects.  

Project manager responses suggests that while 65% of long-term studies require sites to make interim phone calls, less than half of these calls actually connect with patients due to a lack of available resources/infrastructure at sites.  

The analysis also suggested that while approximately 5% of a study's budget is normally allocated to the development of patient retention and compliance support materials, less than half of these materials are actually received by the patients. In contrast, studies that employed patient tracking services to call patients by telephone or distribute retention materials by mail directly to patients achieved call connection rates in excess of 90%, and material delivery rates in excess of 94%. Maximizing the cost-effectiveness of retention strategies is even more critical in this era of tight economic focus.

A sponsor started using a patient tracking service one year into its four-year study with a target enrollment of 4,500 patients, when higher than expected patient drop-out and LTFU rates were observed. Subsequently, 90% of patients were registered with the patient tracking service. The sponsor chose to reduce the burden on sites associated with the distribution of retention materials by using the tracking service to make interim phone calls and distribute study newsletters. After three years, the sponsor has been able to stay in contact with 99% of registered patients, compared with only 67% of those who were not registered. In addition 85% of the patients registered with the tracking service were still on protocol at the end of the study opposed to 47% of those who were not. Further details of this case study are available in the Case Study sidebar.  

Case Study: Early Intervention Can Improve LTFU Rates			

As study follow-up periods get longer there is an increased risk that sites may not be able to stay in touch with their patients. Unfortunately, since most long-term studies are conducted to quantify infrequent safety or clinical outcomes, the inability to account for even small numbers of patients can cause a study to fail. Results show that proactive patient tracking can have a lasting and positive impact on reducing the detrimental effect of patient drop out and LTFU. 

 is Director, Strategic Accounts, e-mail: 

 is General Counsel both at BINTO USA Inc., 66 Witherspoon Street, Suite 317, Princeton, NJ.

1. V. Kristman, M. Manno, and P. Cote, "Loss to Follow-Up in Cohort Studies: How Much is Too Much?," 

Postmarket Requirements and Commitments, 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/ucm064633.htm

Pharmacovigilance for Medicinal Products for Human Use, 

Chapter 3, Part I, Volume 9A of Eudralex, 

http://ec.europa.eu/health/documents/eudralex/vol-9/index_en.htm

4. Elizabeth Moench, "The Business of Recruitment," 

Applied Clinical Trials, Trends in Subject Recruitment,

A 10-fold reduction in LTFU rates was observed in clinical trials that used patient tracking services.

Lost to Follow-Up Survey Results

, MD, to the role of Chief Medical Officer in addition to his current role as Vice President of Global Cardiology.

has been hired as Executive Director of Regulatory Affairs at 

 (Deerfield, IL) to lead the company's regulatory and pharmacovigilance efforts.

(Princeton, NJ) as Executive Medical Director, Neuroscience. The company has also appointed 

, PhD, as Vice President, Bioanalytical Services.

, MD, co-founder of ClinPhone, will join its Board of Directors. 

• Bringing with him more than 30 years of experience in preclinical safety, and testing, 

(Evreux, France) as Director of Scientific Projects and Client Consulting. 

, PhD, to its oncology leadership team as Senior Vice President, Clinical Development, where he will leverage his extensive oncology expertise to support the company's oncology development and service delivery efforts in Europe and Asia Pacific. 

, formerly Chief Operating Officer and Executive Vice President at Covance, as the company's new Chief Executive. 

as Vice President of Clinical Development for Asia Pacific. He will be based in Singapore and will provide strategic leadership and operational oversight for PPD's Phase II-IV business in the region. 

• With over 30 years of experience in the contract research organization and pharmaceutical industries, 

 PhD, has been appointed Vice President of Global Bioanalytical Services  at 

(Brigend, UK), has appointed two new Project Managers, 

, MD, as a member of the company's supervisory board to help the company position its strategic assets. 

 (Philadelphia, PA) has formed a partnership with 

 (San Francisco, CA) to deliver efficient web-based solutions for clinical trial patients. 

 (Salt Lake City, UT) to enable quicker and safer evaluations of potential new medications in patients.

 (London, UK) made an additional financial investment in 

, (San Francisco, CA) to strengthen its strategic partnership with the company established in April 2009. 

(New York, NY) has entered into a strategic alliance with 

 (AMI) (Ardsley, NY) to bring together AMI's instrumentation with Clinilabs' core laboratory.

, Chairman and Chief Executive Officer, received the Ernst & Young Master Entrepreneur of the Year Award at the 2011 New Jersey program's 25th anniversary gala.

 (Ravensburg, Germany) has received the Frost & Sullivan 2011 European Prefilled Injection Systems Customer Service Leadership Award for best practices in its collaboration with global customers.

Association for the Accreditation of Human Research Protection Programs 

(Washington, DC) has awarded five organizations with full accreditation including 

Beijing YouAn Hospital, Capital Medical University 

Veterans Health Administration Central Office Human Research Protections Program

 (New York, NY) announced the results of the IntraLinks Global Investigator Site Survey which highlights the need for the adoption of web-based clinical trial document exchange tools to drive efficiencies and increase productivity.

 (Cary, NC) announced the availability of its 3rd Annual CRO Quality Benchmarking Report. The 2011 version of the report profiles 169 pharmaceutical and biotechnology professionals and their experiences with dozens of small, mid-size, and large CROs. 

(New York, NY) has published its Q2, 2011 marketing intelligence report for the pharmaceutical and biotech CRO/CMO industry. The release of this second quarterly report enables companies buying the research to see developing trends from the Q1 report, as well as the overall key survey research that provides benchmark metrics for customer perception and customer awareness in the industry.

 (Boston, MA) has released the first edition of 

Global Regulatory Systems: A Strategic Primer for Biopharmaceutical Product Development and Registration

, a guide to the complexities of drug approval and regulation.

 (San Francisco, CA) has announced that a number of pharmaceutical industry leaders including GlaxoSmithKline and Roche have agreed to participate in the creation of a set of industry patient enrollment benchmarks based on real-world clinical performance data. Each of the initial sponsors will contribute their historical enrollment data, which will be anonymized, aggregated, and made available to all participants via DecisionView's StudyOptimizer for use in benchmarking, planning, and forecasting clinical trial enrollment. 

 (Princeton, NJ) bioanalytical laboratory in Quebec City, Canada, has received formal recognition from the Standards Council of Canada for its compliance with the Organization for Economic Co-operation and Development Principles of Good Laboratory Practice.

(Chicago, IL) has established Bordeaux Clinical Research Network, a service platform dedicated to clinical trials in the healthcare industry. It aims to fulfill the increasing requirements of CROs and healthcare professionals to boost and speed up patient inclusion in phase I to IV clinical trials, while still ensuring compliance with all applicable quality standards.

A paper, "Practical Considerations for Clinical Trial Sites Using Electronic Health Records Certified for Clinical Research," was released by the 

(Friesenheim, France) that speaks directly to clinical research investigative sites regarding the use of electronic health record systems.

 (Limerick, Ireland), provider of technology solutions that boost investigator site performance to enhance investigator site performance and quality.

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and News Update September 2011

Recently, pharmaceutical companies have started to embrace social media, in part due to Facebook's agreement to allow closed walls on pharma Facebook pages. This prevented people from commenting publicly on the site, thus avoiding customer complaints about drug side effects. But in an impromptu move, Facebook decided last month to take away pharma's special rights, causing many to panic and jump ship. 

Companies such as AstraZeneca decided to close down their Facebook pages rather than risk possible adverse event reports (AER), while others such as Pfizer have opted to keep their page but closely monitor it for any unacceptable comments.  

So what's pharma so afraid of, and are their fears warranted? Companies are concerned that comments about negative side effects will mean an onslaught of AERs that will need to be submitted to the FDA. But according to a podcast from 

with Elizabeth Garrard, Chief Safety Officer for Drug Safety Alliance Inc., a study showed that only one in 500 messages could be reportable as an AE. This is because most messages lack one or more of the four items needed in order to be considered a reportable AE: the drug, adverse event, identifiable patient, and identifiable reporter. 

Despite these statistics, Stewart Geary, Vice President and Global Head of Pharmacovigilance at Eisai Co., Ltd., notes that even though there may only be a handful of reports that would need to be submitted to the FDA, "the variety of international regulations and their various interpretations by pharmacovigilance inspectors from regulatory agencies potentially require that a company collect, save, and periodically evaluate in aggregate all such information even when it is fragmentary and does not allow meaningful assessment." 			

Geary goes on to comment on the lack of regulatory guidance in this space, "I think that this is an example of how complex regulation inhibits the ability to take advantage of technological innovation." 

Open Facebook walls could bombard companies with AERs.

Pharma Companies Lose Facebook Privileges

In January, Merck BioVentures, a division of Merck that delivers biosimilars, entered into an alliance with Parexel to provide clinical development services. In news reports, it was noted that Merck hopes to have five biosimilars in late stage trials in 2012, with hopes to launch products in 2015. 

 after this announcement, Parexel CEO Josef Von Rickenbach said that the company's regulatory expertise, as well as its biosimilars domain knowledge, influenced Merck to choose Parexel for this alliance. "Merck obviously has a close collaboration with us and is entrusting us to the development of their portfolio in biosimilars. And that's a big deal, any way you look at it, for both companies."  

To achieve the milestones that Merck requires, Parexel created a dedicated Merck BioVentures business unit within Parexel. Said Rickenbach, "It's at the current time relatively small because we're still in the planning stages and in the regulatory clarification stages." 

Regulatory clarification would translate to mean that FDA does not have a formal guidance on biosimilars in place, so most pharmaceutical companies' decisions in this area rely on looking at the EU's biosimilar path as it is much more advanced. To date, Europe has approved 14 biosimilars with no significant safety issues reported (save for one that was a follow-on biologic called Eprex, an epoetin alfa to treat anemia, which suffered from a significant safety issue in France). The biosimilar developments that have been reviewed in Europe include three classes—human growth hormones, epoetins, and recombinant insulins. With a growth hormone already approved in the United States, as well as the July 2010 FDA approval of a low-weight molecular heparin (enoxaparin), there are pathways to negotiate toward approval. 

The New England Journal of Medicine reveals list of biosimilar guidelines.

Applied Clinical Trials-09-01-2011